Determinants of operative mortality for patients undergoing aortic valve replacement

J

THoRAc CARDIOVASC SURG

89:400-413, 1985

Determinants of operative mortality for patients undergoing aortic valve replacement Discriminant analysis of 1,479 operations The influence of 35 preoperative and intraoperative characteristics on operative mortality risk after 1,479 isolated aortic valve replacement procedures (1967 to 1981) was investigated utiUzing univariate and multivariate logistic regression analyses. Mean age at operation was 58 ± 13 years; 72 % of patients were men. Physiology was classified as aortic stenosis (58%), regurgitation (30%), or both (9%). The overaU operative mortality rate was 7 % ± 1 %, but there were substantial differences in operative mortality rates among physiological subgroups (aortic regurgitation, 10% ± 2%; aortic stenosis, 6% ± 1%; stenosis/regurgitation, 5% ± 2%). Independent determinants of operative mortality rate in the entire group were advanced New York Heart Association functional class, renal dysfunction, physiological subgroup, atrial fibrillation, and older age. In the aortic regurgitation subgroup, functional class, atrial fibriUation, and operative year were independent predictors. In the aortic stenosis subgroup, the significant determinants were functional class, renal dysfunction, age, prosthetic valve dysfunction, and absence of angina. Concomitant coronary bypass grafting, previous operation, endocarditis, and ascending aortic replacement had no independent predictive effect on operative mortality rate. Thus, the early results of aortic valve replacement can be related to several specific variables describing the functional and physiological status of the patient. Operative mortality rate is not independently related to previous operation or concomitant operative procedures. Specific differences in risk factors exist among the various physiological subgroups, probably reflecting the pathophysiology of the different hemodynamic lesions. This information should provide for a more rational approach to aortic valve replacement, at least in terms of early risk/ben~fit deliberations.

William C. Scott, M.D.,* D. Craig Miller, M.D., Axel Haverich, M.D.,** Keith Dawkins, M.R.C.P., R. Scott Mitchell, M.D., Stuart W. Jamieson, M.D., Philip E. Oyer, M.D., Edward B. Stinson, M.D., John C. Baldwin, M.D., and Norman E. Shumway, M.D., Stanford, Calif.

Although the operative mortality (OM) rate for aortic valve replacement (AVR) has decreased in recent years.!" OM risk still constitutes an important element in the decision making process before proceeding with

From the Department of Cardiovascular Surgery, Stanford University School of Medicine, Stanford, Calif. Read at the Tenth Annual Meeting of the Western Thoracic Surgical Association, Maui, Hawaii, June 20-23, 1984. Address for reprints: D_ Craig Miller, M_D., Department of Cardiovascular Surgery, Stanford University School of Medicine, Stanford, Calif. 94305. 'Current address: Thoracic and Cardiovascular Associates of New Haven, 40 Temple Street, New Haven, Conn. 06510. •• Department of Cardiovascular Surgery, Hannover Medical School, Hannover, West Germany.

400

valve replacement. i.a, 7-12 Increased OM risk has been associated with a number of patient, temporal, and operative factors, 1-4, 6-9,11-21 but interdependent variables have resulted in conflicting findings. Only a few studies- J, 9, II, IJ have defined variables that are independently related to increased risk of OM, This study was designed to identify the independent preoperative and intraoperative risk factors of OM during the modern era of AVR. Additionally, the large number of patients in this study permitted meaningful comparison of the independent risk factors in the various physiological subgroups. Materials and methods Patient population. A total of 1,467 patients underwent 1,479 AVR procedures between 1967 and 1981

Volume 89

Aortic valve replacement

Number 3

40 1

March, 1985

150 125

NUMBER OF PATIENTS

100 75 50 25

o

AS

67 68 69 70 71 72 73 74 75 76 77 78 79 80 81

~I AR

AS/ AR

YEAR

NO PHYSIOLOGY

Fig. 1. Analysis of entire aortic valve replacement group by operative year according to physiological subgroup. AS, Aortic stenosis. AR, Aortic regurgitation. ASjAR, Mixed AS and AR.

(Fig. 1). Another 278 patients receiving various other types of valve substitutes were excluded. Patients with previous valve replacement or other cardiac operations and those undergoing concomitant coronary artery bypass grafting or ascending aortic replacement were included. Standard surgical techniques were employed utilizing either topical hypothermia alone or single-dose crystalloid cardioplegia supplemented with topical hypothermia for myocardial preservation. Starr-Edwards (Model 1260) valveswere used prior to 1971; after 1975, porcine xenograft valves were utilized exclusively. During the transition period (1971 to 1975), both valve types were used. Twenty-nine preoperative (including nine catheterization parameters) and six intraoperative characteristics were investigated with respect to OM rate (Table I). OM was defined as death before discharge from the hospital regardless of time postoperatively or within 30 days of operation. Dichotomous variables were coded: yes or no; male or female. New York Heart Association functional class (FC) was coded 1 to 4; physiology was labeled as mixed aortic stenosis/regurgitation (AS/ AR), stenosis (AS), and regurgitation (AR). Age, operative date, aortic cross-clamp time, and catheterization data were evaluated as continuous variables. An index of "complete revascularization" was defined as the number of vessels bypassed divided by the number of vessels diseased (by angiography). Average age was 59 ± 13 years. The distribution of patients by operative year and physiology is illustrated in Fig. 1. Patients were judged to have renal dysfunction if the blood urea nitrogen level was greater than 40 mg/dl or serum creatinine was greater than 3 mg/dl, Hepatic dysfunction was present if total bilirubin was greater

than twice normal. Thromboembolism included both peripheral and central arterial thromboembolic events. Statistical methods. All continuous data are expressed as mean plus or minus one standard deviation. Error bars in the figures are plus or minus 70% confidence limits (discrete variables) or plus or minus one standard deviation (continuous variables). Differences between variables were assessed by Fisher's exact test, chi square contingency analysis, or nonpaired t test corrected for multiple comparisons (where appropriate). All variables were first tested individually (univariate analysis) by the Duncan-Walker logistic regression analysis." Pearson correlation coefficients were calculated between all possible pairs of significant univariate determinants to avoid inclusion of two variables carrying similar information (r > 0.7). Covariates that were found to be significant (p < 0.05) or marginally significant (0.05 < P < 0.20) when analyzed singly were then tested by a forward stepwise logistic regression discriminant analysis." The relationship between the dependent variable (probability of OM) and the independent variables is described by the sign of the t statistic, a negative value implying an inverse relationship. In the multivariate analysis, an F statistic greater than 3.84 corresponds approximately to a two-tailed p value of less than 0.05. The multivariate determinants were ranked according to their F statistics to indicate relative statistical predictive power, but the logistic coefficient of each significant variable was listed as well. Distribution of patients. AS was the predominant hemodynamic lesion in the majority of patients (60% [884/1,479]), AR accounted for 29% (n = 432), 10% were classified as AS/AR (n = 146), and there was no primary hemodynamic abnormality in 1% (Fig. 2). The

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Scott et af.

AR (29.2%1

AS (59.8%)

Fig. 2. Subdivision of AVR patients by physiological subgroup. Abbreviations as in Fig. 1. patient population was divided into two subsets for assessment of change over the 14 years' time span. The early operative era (1967 to 1973) contained 30% of patients, with 70% in the later operative era (1974 to 1981) (Fig. 1). The proportion of AS patients decreased slightly (69% to 56%, p < 0.001) over the period of study, whereas the proportion of AS/AR patients increased (5% versus 12%, p < 0.001). There was no significant change in the proportion of AR patients between the early and late subsets (Fig. 3). Preoperative characteristics. Minor differences existed between the AS and AR subgroups in the distribution of patients by FC (Table I). The mean age in the AS subgroup (63 ± 11 years) was significantly older than that in the AR· group (52 ± 15 years) (p < 0.001). There was little difference in the gender distribution among the subgroups, with the male:female ratio being 3:1. Angina was present in 45% of patients. AS patients had a higher incidence of angina than did AR patients (55% versus 29%, p < 0.0001). Congestive heart failure was present in the majority of patients, with no significant difference in incidence between the physiological subgroups. There also were no significant differences in the incidence of hypertension, hepatic dysfunction, atrial fibrillation, or remote and/or recent myocardial infarction among the physiological subgroups. The AS subgroup (11% ± 1%) had a higher incidence of diabetes mellitus than did either the AR group or the AS/AR group (p = 0.024, P = 0.037). The AR subgroup had more than twice the incidence of renal dysfunction than did the AS group (7% versus 3%, p = 0.0005). The overall incidence of endocarditis was 6%, but it was 17% in the AR group versus 0.2% in the AS and 3% in the AS/AR groups (p < 0.0001, P = 0.0001). Emergency operation was necessary twice as frequently in the AR subgroup as in the AS subgroup (6% versus 3%, p = 0.004). Five percent of patients had prosthetic valve

dysfunction, but this was also more common (12% ± 0.2%) in the AR subgroup. There were no significant differences among the physiological subgroups in the incidence of either concomitant mitral valve disease or preoperative thromboembolism. A larger proportion of AR patients (16%) had undergone previous cardiac operations than in either the AS (4%) or AS/AR (7%) subgroups (p
Volume 89

Aortic valve replacement

Number 3 March. 1985

403

OPERATIVE MORTALITY BY PHYSIOLOGY NS

12 10 PERCENT OF GROUP

B 6 4 2 0

-

.',<.01

ili p=.05',

-

-

I

67-73

AS

AR

OPERATIVEMORTALITY BY PHYSIOLOGY 25 AND RANGEOF OPERATIVE YEARS r=-1

p = .00 0 3

20

5

o

AS

AR

ASI AR ALL

74-81

ASI AR ALL DISTRIBUTION OF PATIENTS BY PHYSIOLOGY BO AND RANGE OF OPERATIVEYEARS 70

r-----; p<.0001

60 50 40 30 20 10

PERCENT 15 OF GROUP 10

W\3888l

o

NS r-----;

NS

r--"1

AS

AR

AS/AR NONE

PHYSIOLOGY

Fig. 3. Operative mortality according to physiological subgroup and operative era. Distribution of patients by physiological subgroup and operative era is also illustrated. NS, Nonsignificant. Other abbreviations as in Fig. 1. cardiac output and 12% to arrhythmias (Table II). No significant differences in cause of death were seen among the subgroups. Determinants of OM. All AVR patients. In the univariate analysis, advanced disability (high Fe), the presence of renal dysfunction, congestive heart failure, atrial fibrillation, myocardial infarction, or AR physiology predicted a greater likelihood of OM (Table III). Emergency operation, prosthetic valve dysfunction, earlier operative date, and older age were also predictors of increased OM when considered individually. Endocarditis, ascending aortic replacement, thromboembolism, and the number of coronary bypass grafts were possibly significant (0.05 < P < 0.20) and were included in the multivariate analysis. The presence of diabetes mellitus, hypertension, hepatic dysfunction, angina, concomitant mitral valve disease, previous cardiac operation, and concomitant bypass grafting had no influence on OM rate. In the multivariate analysis, FC was clearly the strongest statistical determinant of OM rate (p < 0.001), along with renal dysfunction (p = 0.002), atrial fibrillation (p = 0.007), and physiology (p = 0.004, AR > AS > AS/AR) (Table III). Older age was a weaker, but significant, determinant of OM (p = 0.025). Thus, the apparent relationships between OM and congestive heart failure, myocardial infarction, emergency operation, prosthetic valve dysfunction, year

of operation, endocarditis, ascending aortic replacement, thromboembolism, and number of bypass grafts (suggested by the univariate analysis) were only indirect correlations. AS subgroup. The strong univariate determinants of OM in the AS subgroup were similar to those for the group as a whole: FC, renal dysfunction, emergency operation, congestive heart failure, atrial fibrillation, myocardial infarction, age, and prosthetic valve dysfunction (Table III). The marginal determinants, however, differed somewhat: In the AS subgroup, endocarditis, hepatic dysfunction, absence of angina, thromboembolism, and number of bypass grafts emerged as possibly significant. Advanced FC (p < 0.001) remained the most statistically significant independent determinant of OM in the multivariate analysis, along with age (p = 0.001) and renal dysfunction (p = 0.013). Atrial fibrillation, however, did not contain any significant independent predictive information in the AS subgroup. Prosthetic valve dysfunction (not significant in the total group) was a significant, independent predictor in the AS subgroup (p = 0.046), as was absence of angina (p < 0.05). Emergency operation, congestive heart failure, and myocardial infarction (although highly significant in the univariate analysis) were not significant in the multivariate analysis and thus did not reflect independent predictive information.

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Table I. Selected patient characteristics subdivided according to physiological subgroup Percent of group Characteristics

All In = /,479)

Gender: male NYHA functional class I II III IV

Angina Congestive heart failure Hypertension Diabetes mellitus Renal dysfunction Hepatic dysfunction Atrial fibrillation Thromboembolism Myocardial infarction Physiology AS AR AS/AR Previous cardiac operation Concomitant CABG Concomitant MV disease Concomitant As Ao Repl Prosthetic valve dysfunction Endocarditis Left ventriculography LV dysfunction* Coronary angiography CADt Emergency operation Cardioplegia

AS In = 884)

AR In = 432)

73

72

6 36 49 10 45

4 36 51 10 55

72

72

24

24

9

II

4

3 2 6 5 17

36 44 12 29 73 26 7 7 2 7 5 14

2 6

6

16

AS/AR In = /46)

74

73

8

6 35 53 6 43 73

23 5 5 2 7 4 19

60 29 10 27

4

16

33

18

24

3 8

3 2

4 22

6 6

9

5

13

6

0.2 59

62 45 67 44 4

26

44

73 48 3

28

12 17 66 48 54 34 6 22

7

0.7 3

82 46 71 39 3

25

Legend: NYHA, New York Heart Association. AS, Aortic stenosis. AR, Aortic regurgitation. AS/AR, Mixed AS and AR. CABG, Coronary artery bypass grafting. CAD, Coronary artery disease. LV, Left ventricular. MV, Mitral valve. As Ao Rcpl, Ascending aortic replacement. 'Percent of patients who had left ventricular angiography. tPercent of those who had coronary arteriography.

AR subgroup. There were fewer predictive covariates in this subgroup, but FC, atrial fibrillation, and renal dysfunction again were strong determinants of increased OM in the univariate analysis (Table III). The significance of congestive heart failure, thromboembolism, and supplemental cardioplegia was marginal. It should be noted that (earlier) year of operation was highly significant in this subgroup. Age, emergency operation, prosthetic valve dysfunction, and myocardial infarction had no effect on probability of OM for patients with AR. In the multivariate regression analysis, FC (p = 0.004), year of operation (p = 0.013), and atrial fibrillation (p = 0.016) were the only significant independent determinants of OM; these covariates had relatively equal statistical predictive power (Table III).

Renal dysfunction (which was a strong predictor of OM in the entire group and in the AS subgroup) was not a significant independent determinant in the AR subgroup. Cardioplegia did not attain independent statistical significance. AS/AR subgroup. This subgroup contained a relatively small number of patients and operative deaths. FC was again the strongest univariate determinant of OM, along with myocardial infarction, diabetes mellitus, renal dysfunction, and advanced age (Table III). Marginally significant determinants included concomitant coronary bypass grafting, emergency operation, endocarditis, and number of bypass grafts. The multivariate analysis yielded only three significant independent determinants of OM: FC, myocardial infarction, and diabetes mellitus (Table III). FC

Volume 89 Number 3 March, 1985

Aortic valve replacement

100 80

---

AS

..----. NS

NS

..----. ;I.

60 l40 I-

PERCENT OF GROUP

20 0 100

60

--

40

~

1_ 80

20

o

67-73

---

~

NS ..----.

~

NS

r=-"1

Ii

ALL

p=0.001

..----.

I-

''-

r

~ L---

IORII

p=0.02 ;::E

r

~

L---L..

AS/AR

..----.

..----.

p=0.02

--

~

--

AR

~

~

;::I

405

;:r.

L--

IORII

III OR IV

..----.

p=0.001

mORIV

FUNCTIONAL CLASS

74-81

Fig. 4. Effect of operative era on New York Heart Association functional class by physiological subgroup. Abbreviations as in Figs. I and 3.

Table II. Cause of operative death in the various physiological subgroups Cause

ASI%) In = 884)

ARI%) In = 432)

AS/AR 1%) In = /46)

None 1%) In = /7)

Low output syndrome Myocardial infarction Arrhythmia PYE Sepsis Technical Pulmonary embolus Multisystem failure Miscellaneous

16 (30)* 2 (4) 6 (II) 0(0) 8 (15) 2 (4) 0(0) 10 (19) 9 (17)

20 (46) 0(0) 5 (12) 2 (5) 5 (12) I (2) 2 (5) 3 (7) 5 (12)

3 (43) 0(0) I (14) 0(0) 0(0) 0(0) 0(0) I (14) 2 (29)

I (100) 0(0) 0(0) 0(0) 0(0) 0(0) 0(0) 0(0) 0(0)

Total

53

43

7

AI/I%) In = /.479)

40 2 12 2 13 3 2 14 16

(38) (2) (12) (2) (12) (3) (2) (14) (15)

104

Legend: AS. Aortic stenosis. AR. Aortic regurgitation. AS/ AR. Mixed AS and AR. PVE. Prosthetic valve endocarditis. "Numbers in parentheses indicate percent of deaths in each subgroup.

(p < 0.001) was the most statistically significant predictor by far. The other two determinants were equal in predictive strength. Specific features in selected subpopulations. The mean aortic cross-clamp time was 64 ± 20 minutes. The AS/AR subgroup had a shorter aortic cross-clamp time than did the AR subgroup (p = 0.016), but crossclamp time was not significantly different between the AS and AR subgroups (Fig. 5). Cross-clamp times increased significantly over the years (except in the AS/AR subgroup), undoubtedly because more patients underwent concomitant coronary bypass grafting in the more recent years. Ischemic arrest time had no significant influence on OM rate in the AS or AS/AR subgroups (univariate analysis);however, arrest time is correlated significantly with OM in the entire group and in the AR subgroup

(p < 0.0001, P = 0.0001). Adding aortic cross-clamp time to the multivariate regression analyses for the total group and for the AR subgroup resulted in identifying longer cross-clamp time as an independent predictor of OM without altering the significance of the other determinants (p < 0.0001 for both). Cardioplegia was used in combination with topical hypothermia in 26% ± 1% of patients (Table I). Cardioplegia had no significant influence on OM in the AS or AS/AR subgroups or in the entire group, but a possible salutary effect was suggested by the univariate analysis for the AR subgroup (Table III). In the multivariate analysis, however, this possible link between cardioplegia and lower OM was not significant. Left ventricular angiography was performed in 62% ± 1% of patients but varied significantly among

The Journal of Thoracic and Cardiovascular Surgery

406 Scott et a/.

Table

m. Determinants of operative mortality for patients

undergoing aortic valve replacement

Univariate

I

Variable

Multivariate p

F

NYHA functional class Renal dysfunction Physiology Atrial fibrillation Age Emergency operation CHF Myocardial infarction PVD Operative year Thromboembolism No. of CABGs Endocarditis Asc Ao Repl

3.68 2.10 -2.06 -1.73 1.66 -1.38 1.29

All patients <0.001 <0.001 0.007 <0.001 <0.001 <0.001 <0.001 <0.001 0.036 0.039 0.083 0.096 0.166 0.198

NYHA functional class Age Renal dysfunction PVD Angina Emergency operation CHF Myocardial infarction Atrial fibrillation Endocarditis Hepatic dysfunction Thromboembolism No. of CABGs

6.84 4.63 -4.19 -2.38 1.70 -4.10 -3.06 3.06 -2.25 -1.95 -1.82 -1.56 1.49

AS subgroup <0.001 <0.001 <0.001 0.Ql7 0.089 <0.001 0.002 0.002 0.024 0.051 0.068 0.119 0.136

NYHA functional class Operative year Atrial fibrillation Renal dysfunction CHF Cardioplegia Thromboembolism

3.40 -3.20 -2.89 -2.43 -1.75 1.61 -1.39

AR patients <0.001 <0.001 0.004 0.Ql5 0.081 0.107 0.164

NYHA functional class Myocardial infarction Diabetes mellitus Renal dysfunction Age at operation Concomitant CABG Emergency operation Endocarditis No. of CABGs

3.68 2.76 -2.49 -2.49 2.28 -1.94 -1.65 -1.45 1.30

AS/AR subgroup <0.001 0.006 0.013 0.013 0.023 0.052 0.100 0.148 0.192

8.14 -5.74 -2.70 -3.78 3.36 -4.00 ~3.82

I

p

I

Coefficient

40.37 10.11 8.33 7.31 5.02

<0.001 0.002 0.004 0.007 0.025 NS NS NS NS NS NS NS NS NS

1.10 -0.55 -0.59 -0.44 0.022

29.80 10.67 6.24 4.01 3.75

<0.001 0.001 0.013 0.046 0.053 NS NS NS NS NS NS NS NS

1.43 0.062 -0.70 -1.15 0.32

8.23 6.26 5.85

0.004 0.013 0.016 NS NS NS NS

0.69 -0.12 -0.59

31.04 18.38 14.99

<0.001 <0.001 <0.001 NS NS NS NS NS NS

3.81 -1.59 -1.47

Legend: NYHA, New York Heart Association. CHF, Congestive heart failure. PYD, Prosthetic valve dysfunction. CABG, Coronary artery bypass graft. Asc Ao Repl. Ascending aortic replacement.

the physiological subgroups (the AS/AR subgroup had the highest frequency [82%], AS the least [59%], and 66% in the AR subgroup [p < 0.0001]) and by operative year (Fig. 6). Of those patients who had a ventriculogram, 45% had segmental and/or generalized left

ventricular wall motion abnormalities (defined as left ventricular dysfunction in this report). The incidence of left ventricular dysfunction increased significantly (31% versus 48% overall, p = 0.0002) over the years in all subgroups.

Volume 89 Number 3 March, 1985

Aortic valve replacement

NS

100 TIME

80

(minutes)

60

407

PHYSIOLOGY

NS p=O.016 ' .------. .------.

40 20 OL---''':-:''-"",,:,,:~~~~~---'

AR

AS

100 TIME

80

(minutes)

60

AS/AR

PHYSIOLOGY & OPERATIVE RANGE

NS p
p
,..----.

ALL

SURVIVORS vs. NON-SURVIVORS

NS

.......---.

~

p
40 20 0

AS

AR

AS/ AR

ALL

c::=:J 67-73

AS

AR

AS/AR ALL

c::=:J SURVIVORS IlIlil!l!l!l!l! NON-SURVIVORS

PHYSIOLOGY

~74-81

Fig. 5. Aortic cross-clamp time as a function of physiological subgroup, operative era, and survival status. Abbreviations as in Figs. 1 and 3.

120 100 PERCENT OF GROUP

LV ANGIOGRAPHY BY RANGE OF OPERATIVE YEARS

LV DYSFUNCTION BY ANGlO BY RANGE OF OPERATIVE YEARS

.--. .--. .--..--.

p<.001

p<.0001 p<.003 p<.0001

80

.--. .--. .--. .--.

p=.017 p=.052 p=.010 p=.OOO2

60 40 20 0 AS

AR

AS/ AR

ALL

AS

AR

AS/ AR

ALL

PHYSIOLOGY

67-73 74-81

Fig. 6. Incidence of left ventricular angiography and dysfunction according to physiological subgroup and operative era. LV, Left ventricular. Other abbreviations as in Fig. 1.

Left ventricular dysfunction was a significant univariate determinant of OM in the total group and in the AS subgroup (p = 0.0002, p = 0.0021). Since these patients represented only a relatively small, selected subpopulation, this variable was not entered into the multivariate analysis. Complete catheterization data were available in only 70% of patients; since this subpopulation represented a selected group of patients, the data again were not entered into the multivariate analysis. Figs. 7 and 8 illustrate the catheterization data according to physiological subgroup and OM. Right heart pressures were

consistently higher in the nonsurvivors, as were pulmonary capillary wedge and left ventricular end-diastolic pressure. Cardiac index was only minimally helpful in distinguishing between survivors and nonsurvivors in the AS and AS/AR subgroups, and left ventricular systolic pressure had no discriminating value. Coronary arteriography was performed in 67% ± 1% of patients, more frequently in the AS (73%) and AS/AR (71%) subgroups than in the AR subgroup (54%) (p < 0.0001, p = 0.0009) (Fig. 9). The AR subgroup had a lower incidence of coronary artery disease (34%) than did the AS subgroup (48%)

The Journal of

408

Scott et al.

Thoracic and Cardiovascular Surgery

RIGHT A TRIAL PRESSURE 20 r - - - - - - - - - - - - - ,

p<.026

NS

p=.011 p=.002

,--, ,--, ,--, ,--,

15 PRESSURE (Torr) 10

5

c==J SURVIVORS

~ NON-SURVIVORS

o

AS AR AS/AR ALL PULMONARY ARTERY SYSTOLIC PRESSURE PULMONARY ARTERY MEAN PRESSURE

100

p<.OO1 p=.014 p=.007p<.001

..----, ,--, ,--, ,--,

75

80 r - - - - - - - - - - - - - ,

40

25

20

o

AS

AR

AS/AR

p<.OO1 p=.OO8 p=.007 p<.001

60

PRESSURE (Torr) 50

,--, ,--, ,--, ,--,

o

ALL

AS

AR

AS/AR

ALL

PHYSIOLOGY

Fig. 7. Right heart catheterization data: Survivors versus nonsurvivors. Abbreviations as in Figs. 1 and 3.

c::::J PRESSU;:..:R.:.:E=----, (torr) PULMONARY WEDGE MEAN PRESSURE p
PRESSURFE (torr)

30

20

20

10

10

o

PRESSURE (torr)

300

AS

AR

AS/ AR

ALL

LEFT VENTRICULAR SYSTOLIC PRESSURE NS NS NS NS

~~~....------.

o OUTPUT

SURVIVORS

~ OPERATIVE DEATHS

---, LEFT VENTRICULAR END DIASTOLIC PRESSURE p=O.001 p=O.013 NS p
AS

AR

AS/ AR

ALL

(L/min/m 2,

4

p=O.039

NS

....------.

3 200

2

100

o

AS

AR

AS/AR

ALL

o

AS

AR

AS/AR

ALL

PHYSIOLOGY

Fig. 8. Left heart catheterization data: Survivors versus nonsurvivors. Abbreviations as in Figs. 1 and 3.

(p = 0.0003). Concomitant bypass grafting was performed in 27% ± 1% of all patients, more frequently in patients with AS (33%) than in patients with either AR (18%) or AS/AR (24%) (p < 0.0001, P = 0.035) (Fig. 9). Interestingly, the incidence of coronary artery disease (defined by angiography) did not change over time (Fig. 10), although more patients during recent years had preoperative angiograrns. The proportion of patients

undergoing concomitant coronary bypass grafting, however, did reflect a more aggressive approach to myocardial revascularization (Fig. 10). The most striking difference over time was seen in the AS subgroup, with more than a threefold increase in concomitant bypass grafting. The presence of coronary artery disease had an adverse influence on OM when considered in the entire group (p = 0.0096, univariate analysis). A similar, but

Volume 89

Aortic valve replacement

Number 3 March, 1985

100 80

PERCENT OF

60

GROUP

-

409

CORONARY ARTERIOGRAPHY NS ' ,p
,=.

.:r.

40 .20 '0

100

PERCENT OF

GROUP

80

AS

AR

AS/AR ALL

PRESENCE OF CORONARY ARTERY DISEASE BY CORONARY ARTERIOGRAPHY NS

CONCOMITANT CORONARY ARTERY BYRASS p=O.035

60 40 20 O'--........JL.-lL--...I.-..L...........Io........ _

AS

AR

......L...---J'-----JIoooooooI'--_ _"O"-

AS/AR ALL

AS

AR

"'"--~

AS/AR ALL

PHYSIOLOGY Fig. 9. Incidence of coronary arteriography, significant coronary artery disease, and concomitant coronary artery bypass grafting by physiological subgroup. Abbreviations as in Figs. I and 3.

insignificant, effect was seen in the AS and AS/AR subgroups (p = 0.10, p = 0.09). Although 82% of patients with angiographic coronary artery disease underwent concomitant coronary bypass grafting, this concomitant procedure had no significant effect on OM. The number of vessels diseased or bypassed also had no significant influenceon OM, although there was a trend toward higher OM with increasing numbers of bypass grafts. Degree of revascularization (mean revascularization index = 0.74 ± 0.6) also had no significant effect on OM. The OM rate for AVR patients with coronary artery disease and concomitant bypass grafting declined over the period of study (Fig. 10). Discussion The patient substrate in this study is representative of patients undergoing AVR in previous studies, and the overall OM rate is comparable.1,3, 7-1 I, 24 The large number of patients in this study allowed definition of high-risk subsets and independent predictive variables that can be used to determine OM risk. FC was the strongest independent predictor of early outcome in the entire group and in all of the physiological subgroups.v 7, II, 13 This one variable represents a synthesis of a number of preoperative patient characteristics; however, the correlation between FC and the other significant univariate characteristics was not high. By virtue of its strong statistical power in the multivar-

iate analysis, FC contains truly independent predictive power. The clinical implications are obvious: In all physiological subgroups, operative intervention earlier in the course of the disease (lower FC) predicts a lower OM risk. This decreased risk must be considered when deciding when to intervene surgically. Earlier operation may be associated with advantages that outweigh other long-term considerations, especially in patients with other independent risk factors, e.g., advanced age, AR, atrial fibrillation, and renal dysfunction. When the entire group was analyzed, several other variables were predictive of OM independent ofFC. Renal dysfunction and atrial fibrillation are usually secondary signs of cardiac decompensation;the presence of either covariateportends a higher likelihood of OM, and they both provide additional information not inherent in FC alone. Advanced age has been reported to be associated with increased OM.3.7. 13 This effect, however, was not modulated by an increase in the incidenceof other risk factors. Age was an independent determinant, most likely due to a general decline in overall reserve of multiple organ systems. Interestingly, many preoperative characteristics were not independently related to OM risk even though they identified "apparent" high-risk subsets (i.e., significant in the univariate analysis only), including emergency operation, congestive heart failure, myocardial infarc-

The Journal of

4 10 Scott et al.

Thoracic and Cardiovascular Surgery

CORONARY ANGIOGRAPHY

p
100 80

PERCENT

OF

60

GROUP

40

I

20

o 100 PERCENT

OF

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PHYSIOLOGY

Fig. 10. Incidence of coronary arteriography, significant coronary artery disease, and concomitant coronary artery bypass grafting by operative era. CAD, Coronary artery disease. Other abbreviations as in Figs. I and 3. tion, year of operation, and prosthetic valve dysfunction. The information contained in these variables was redundant with that in the truly independent determinants. When FC was omitted from the multivariate analysis, all of these other factors became significant determinants to varying degrees. Th\!S, FC reflects information inherent in all of these factors as well as that in other, undefmed characteristics. Previous cardiac operation, 11,16 gender.v' endocarditiS,II, 16.18 concomitant coronary artery bypass grafting,' and ascending aortic replacement" have previously been reported to influence OM rate. In this study, these variables were found to portend no increased OM risk. Concomitant bypass grafting in the AS / AR subgroup and endocarditis in the AS and the AS/AR subgroups were univariate predictors of higher risk; however, these variables were not significant independent predictors in any subgroup. Patients with AR had a significantly higher OM rate than did those with AS or AS / AR,7' II and physiological subgroup was a strong independent determinant of OM. This confirms that this effect was a function of the pathophysiology of the hemodynamic valvular lesion itself, and not a manifestation of other secondary complications. In addition to FC, only age, renal dysfunction, prosthetic valve stenosis, and absence of angina were significant independent determinants of OM in the AS subgroup. The AS patients were older, and aortic valve disease in the elderly is usually aortic sclerosis of a

trileaflet valve with predominant stenosis. Thus, it is not unexpected that age plays a relatively more important role in the AS subgroup. Renal dysfunction, frequently a sign of low cardiac output and acute decompensation, would also be expected to be a predictor of poor outcome. A surprising finding in the AS subgroup was the strong relationship between prosthetic valve stenosis or absence of angina and increased OM. The association between prosthetic valve stenosis and increased OM has been described previously,16,18 but in this study this covariate was an independent determinant of OM in patients with both mechanical and tissue valves. Absence of angina also placed the patient with AS in a higher risk category; although we have no clear explanation for this fmding, it is probably related to the myriad of other problems that can prompt consideration of AVR in patients with AS who do not have angina. The determinants of OM in the AR subgroup were different. Atrial fibrillation was a independent determinant in the AR subgroup along with Fe. The strong predictive power of atrial fibrillation was probably related to advanced cardiac disease and cardiomegaly, which previously have been shown to increase OM risk. I, 3. 6. 15, 21 The only other independent determinant identified in the AR subgroup was year of operation, with a substantial reduction in OM rate over time. This fmding can be explained, in part, by the fact that patients with AR presented earlier in the course of their disease during the more recent years. Since year of operation attained multivariate significance, however, it

Volume 89 Number 3

Aortic valve replacement

March, 1985

was indeed an independent determinant of OM irrespective of the influence of lower Fe. The reasons for the independence remain speculative. It is likely, however, that a number of specific and general improvements in preoperative evaluation, intraoperative techniques, and postoperative care have occurred which account for this more pronounced effect in this (higher risk) AR subgroup. In this study, aortic cross-clamp time was an independent predictor in the entire group and in the AR subgroup.ll.1J Since cross-clamp time cannot be predicted preoperatively, this parameter has limited utility in the selection of patients for operation. The use of cardioplegia has been credited with part of the improvement in early survival after AVR by some investigatorsv'tP"; however, others have found no significant effect on either OM6.9 or late survival rate.' Since the majority of patients die of low cardiac output, one might be able to detect differences in OM if cardioplegia produced a dramatic improvement. Comparing continuous topical hypothermia alone with topical hypothermia plus supplemental cardioplegia in concurrent time periods revealed no significant difference in OM. There was a tendency for the cardioplegia-treated patients to do slightly better in the AR subgroup, but this difference was not highly significant (p = 0.10) in the univariate analysis and did not even approach independent significance. Left ventricular systolic dysfunction has been reported to increase OM in patients with AR.15 Our results suggest that left ventricular dysfunction was a predictor in the AS subgroup, in which most patients had relatively well-preserved left ventricular function, but not in the AR subgroup, in which some degree of decreased left ventricular function is not unusual. The effect of coronary artery disease in patients undergoing AVR has been a difficult question to address since a concurrent, controlled series does not exist. Others have reported an increase in OM related to the presence of coronary artery disease,1.19 which is suggested by the univariate analysis of the selected subpopulation in this study that had coronary angiography. Conversely, we did not find any significant influence of concomitant bypass grafting or degree of revascularization on OM, as also reported by others.3,6. 13. 25 Since prolonged aortic cross-clamp time is not without hazard and the benefits of concomitant bypass grafting have not been proved conclusively,'? we have adopted what we believe to be the most rational approach, viz., concomitant revascularization of the myocardial regions in the most jeopardy, usually ignoring critical lesions in nondominant circumflex or right coronary arteries.

4II

Applying these data to the clinical decision-making realm is important. Knowing the characteristics that independently portend a disproportionately high OM rate can help determine the timing of AVR in an intelligent and objective fashion. Such appropriate timing of AVR should minimize operative risk, but, of course, the long-term risks of prosthetic or bioprosthetic valve disease must also be considered. Additionally, the underlying pathophysiology of the disease and the patient's prognosis without AVR must also be integrated into the decision-making process. In summary, the early results of AVR can be related to several specific variables describing the functional and physiological status of the patient. OM rate is not independently related to previous operation or concomitant operative procedures. Some specific differences in risk factors exist among the physiological subgroups; these differences are probably related to the pathophysiology of the different valvular lesions. This information should provide for a more rational approach to AVR, at least in terms of early risk/benefit deliberations. We would like to acknowledge and express sincere appreciation to Marta Gomez, Voy Wiederhold, Rupert Miller, Ph.D., and Suzanne G. McC~rthy for their valuable assistance in the collection and processing of the data in this study.

2

3

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5

6

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REFERENCES Copeland JG, Griepp RB, Stinson EB, Shumway NE: Long-term follow-up after isolated aortic valve replacement. J THORAC CARDIOVASC SURG 74:875-889, 1977 Lytle BW, Cosgrove DM, Loop FD, Taylor PC, Gill CC, Golding LAR, Goormastic M, Groves LK: Aortic valve replacement combined with myocardial revascularization. Determinants oflate morbidity and mortality, 471 patients, 1967-1981 (abstr). J Am Coli Cardioll:631, 1983 Lytle BW, Cosgrove DM, Loop FD, Taylor PC, Gill CC, Golding LAR, Goormastic M, Groves LK: Replacement of aortic valve combined with myocardial revascularization. Determinants of early and late risk for 500 patients, 19671981. Circulation 68: 1149-1162, 1983 Husebye DG, Pluth JR, Piehler JM, SchaffHV, Orszulak TA, Puga FJ, Danielson GK: Reoperation on prosthetic heart valves. An analysis of risk factors in 552 patients. J THORAC CARDIOVASC SURG 86:543-552, 1983 Macmanus Q, Grunkemeier GL, Lambert LE, Teply JF, Harlan BJ, Starr A: Year of operation as a risk factor in the late results of valve replacement. J THORAC CARDIOVASC SURG 80:834-841, 1980 Nunley D, Grunkemeier GL, Starr A: Aortic valve replacement with coronary bypass grafting. J THORAC CARDIOVASC SURG 85:705-711, 1983 Murphy DA, Levine FH, Buckley MJ, Swinski L, Daggett WM, Akins CW, Austen WG: Mechanical valves. A comparative analysis of the Starr-Edwards and Bjork-

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The Journal of Thoracic and Cardiovascular Surgery

Scott et al.

Shiley prostheses. J THORAC CARDIOVASC SURG 86:746752, 1983 Miller DC, Stinson EB, Oyer PE, Moreno-Cabral RJ, Reitz BA, Rossiter SJ, Shumway NE: Concomitant resection of ascending aortic aneurysm and replacement of the aortic valve. J THORAC CARDIOVASC SURG 79:388-401, 1980 Acar J, Luxereau P, Ducimetiere P, Cadihbac M, Jallut H, Vahanian A: Prognosis of surgically treated chronic aortic valve disease. Predictive indicators of early postoperative risk and long-term survival, based on 439 cases. J THORAC CARDIOVASC SURG 82:114-126, 1981 McGoon MD, Fuster V, McGoon DC, Pumphrey CW, Pluth JR, Elveback LR: Aortic and mitral valve incompetence. Long-term follow-up of patients treated with the Starr-Edwards prosthesis. J Am ColI Cardiol 3:930-938, 1984 Wideman FE, Blackstone EH, Kirklin JW, Karp RB, Kouchoukos NT, Pacifico AD: Hospital mortality of re-replacement of the aortic valve. Incremental risk factors. J THORAC CARDIOVASC SURG 82:692-698, 1981 Stone PH, Clark RD, Goldschlager N, Selzer A, Cohn K: Determinants of prognosis of patients with aortic regurgitation who undergo aortic valve replacement. J Am ColI Cardiol 3: 1118-1126, 1984 Kirklin JW: A letter to Helen. J THORAC CARDIOVASC SURG 78:643-654, 1979 Lawrence RS, Mena I, Dengo JA, Walkinshaw MD, Nelson RJ: Noninvasive evaluation of left ventricular function after aortic valve replacement. J THORAC CARDlOVASC SURG 79:504-512,1980 Thompson R, Ahmed M, Seabra-Gomes R, Ilsley C, Rickards A, Towers M, Yacoub M: Influence of preoperative left ventricular function on results of homograft replacement of the aortic valve for aortic regurgitation. J THORAC CARDIOVASC SURG 77:411-421, 1979 Rossiter SJ, Miller DC, Stinson EB, Oyer PE, Reitz BA, Shumway NE: Aortic and mitral prosthetic valve reoperations. Arch Surg 114:1279-1283, 1979 Parr GVS, Kirklin JW, Blackstone EH: The early risk of re-replacement of aortic valves. Ann Thorac Surg 23:319322, 1977 Syracuse DC, Bowman FO, Maim JR: Prosthetic valve reoperations. Factors influencing early and late survival. J THORAC CARDIOVASC SURG 77:346-354, 1979 Miller DC, Stinson EB, Oyer PE, Rossiter SJ, Reitz BA, Shumway NE: Surgical implications and results of combined aortic valve replacement and myocardial revascularization. Am J Cardiol 43:494-501, 1979 Kouchoukos NT, Lell WA, Rogers W J: Combined aortic valve replacement and myocardial revascularization. Experience with a cold cardioplegic technique. Ann Surg 197:721-728,1983 Richardson JV, Kouchoukos NT, Wright JO, Karp RB: Combined aortic valve replacement and myocardial revascularization. Results in 220 patients. Circulation 59:75-81, 1979

22 Crowley J, Hu M: Covariance analysis of heart transplant survival data. J Am Stat Assoc 72:27-36, 1977 23 Dixon WJ, ed: BMDP Biomedical Computer Programs, Program BMDPLR, Berkeley, 1983, University of California Press 24 Rahimtoola SH: Valve replacement should not be performed in all asymptomatic patients with severe aortic incompetence. J THORAC CARDIOVASC SURG 79: I63- I72, 1980 25 Kirklin JW, Kouchoukos NT: Aortic valve replacement without myocardial revascularization (edit). Circulation 63:252-253, 1981

Discussion DR. BRADLEY J. HARLAN Sacramento, Calif

This study combines a large number of patients over a long time frame with sophisticated and exhaustive statistical analysis. It adds to our knowledge about the risk of AVR, and it raises some interesting questions regarding patient selection and conduct of the operation. We have completed a retrospective review of AVR at Sutter Memorial Hospital and, although our study concentrates on late patient outcome and valve performance, there are some interesting comparisons of our group with that of the Stanford group. Over a relatively similar time frame, and with less than half the number of patients, we found that there were some differences among the physiological subgroups undergoing AVR. Perhaps some of these differences are related to matters of definition. I thought it was interesting that there were striking similarities among the proportion of patients who were in FC IV (10% and 13%); the proportion of patients who underwent concomitant coronary artery bypass (27% and 26%); and, over this long time frame, with varying methods of operative technique, the OM rates were 7.7% and 7.8%. In our series of patients, the presence of bacterial endocarditis, the necessity for an emergency operation, or the addition of resection of the ascending aorta all increased the OM. The fact that these variables did not increase OM in the Stanford group is remarkable and commendable. A study such as this not only can define varying risks of surgical intervention, but also can address the question of whether there are any subsets of patients with aortic valvular disease in whom operation is contraindicated. I wonder if the authors might comment on whether there are any extremes, or sets of extremes, within these variables which identify patients with end-stage aortic valve disease in whom the risk of operation is unacceptably high. One of the most interesting aspects of this study relates to myocardial preservation. At the birthplace of topical hypothermia, the addition of cold crystalloid cardioplegia to topical hypothermia did not improve the OM. This, of course, conflicts with the findings of most studies over the past half decade. I wonder whether this disparity is explained by the method of cardioplegia used at Stanford, since only single-dose cardioplegia is used. There is a large body of scientific data,

Volume 89 Number 3 March, 1985

obtained both experimentally and clinically, that supports the use of multidose cardioplegia and myocardial temperature monitoring. There is also a growing body of data that supports the superiority of cold blood cardioplegia over crystalloid cardioplegia in patients who have diminished left ventricular function, left ventricular hypertrophy, and prolonged aortic cross-clamp times. In these groups of patients we tend to use cold blood cardioplegia. Was myocardial temperature monitoring used in this group of patients, and have the results of this study resulted in any change in the method of administering cardioplegia at Stanford? DR. SCOTT (Closing) I would like to thank Dr. Harlan for his kind comments. I will address his second question first, since it is the easier to answer. The method of myocardial preservation used at Stanford now varies from surgeon to surgeon. There are basically two methods: either Dr. Shumway's method of topical hypothermia alone or else topical hypothermia with single-dose crystalloid cardioplegia. Topical hypothermia includes continuous cold saline irrigation with special attempts to keep the entire heart underneath the cold. We do not measure intramyocardial temperatures routinely. However, that work has been done previously, and temperatures usually are kept in the low teens in all myocardial segments. With respect to cardioplegia, we have a concurrent series of patients, some of whom have and some of whom have not had the administration of cardioplegia. About 28% of our patients

Aortic valve replacement

4 13

overall have received cardioplegia, with no differences within the physiological subgroups. Looking at OM rates with and without cardioplegia, there are no differences in the AS, the AS/AR, or the entire group. In the AR subgroup, there is a trend toward a salutary effect of cardioplegia. However, the difference in this AR subgroup is not statistically significant and, when entered into the multivariate analysis, use of cardioplegia was not an independent risk factor. Thus, statistically, there was no effect of cardioplegia. Regarding the question about whether or not we have modified our approach to myocardial preservation, the answer is "no." We still use single-dose crystalloid cardioplegia in addition to topical hypothermia in most of the patients. An interesting finding is that, from our total group of patients, 384 had low-risk multivariate factors. The overall OM risk for this low-risk group of patients was 1.3%.This is a respectable OM for AVR, even without multidose crystalloid or blood cardioplegia. The second question is a little harder to answer. It is important to realize that we were dealing with a 15 year time span, during part of which sophisticated data, in terms of assessment of ventricular function preoperatively, were not available. Thus, pressure volume stress relationships, etc., were not available to add to the multivariate analysis in significant numbers of patients. From the data that we have, there is no way to say who is or is not inoperable, but rather to tell what the relative risk is for each individual risk factor.