Background The independent prognostic value of elevated jugularvenous pressure or a third heart sound in patients with heartfailure is not well established.
Methods We performed a retrospective analysis of the Studiesof Left Ventricular Dysfunction treatment trial, in which 2569patients with symptomatic heart failure or a history of it wererandomly assigned to receive enalapril or placebo. The mean(±SD) follow-up was 32±15 months. The presenceof elevated jugular venous pressure or a third heart sound wasascertained by physical examination on entry into the trial.The risks of hospitalization for heart failure and progressionof heart failure as defined by death from pump failure and thecomposite end point of death or hospitalization for heart failurewere compared in patients with these findings on physical examinationand patients without these findings.
Results In multivariate analyses that were adjusted for othermarkers of the severity of heart failure, elevated jugular venouspressure was associated with an increased risk of hospitalizationfor heart failure (relative risk, 1.32; 95 percent confidenceinterval, 1.08 to 1.62; P<0.01), death or hospitalizationfor heart failure (relative risk, 1.30; 95 percent confidenceinterval, 1.11 to 1.53; P<0.005), and death from pump failure(relative risk, 1.37; 95 percent confidence interval, 1.07 to1.75; P<0.05). The presence of a third heart sound was associatedwith similarly increased risks of these outcomes.
Conclusions In patients with heart failure, elevated jugularvenous pressure and a third heart sound are each independentlyassociated with adverse outcomes, including progression of heartfailure. Assessment for these findings is clinically meaningful.(N Engl J Med 2001; 345:574-81.)
There is concern that physicians are becoming less proficientat performing the physical examination.1,2,3,4 For example,physicians in residency programs have been shown to have poorcardiac auscultatory skills.5,6 This decline in physical-examinationskills may be due in part to an increasing availability andreliance on forms of technology such as echocardiography.1,2,3,4In an era of evidence-based medicine,7 the demonstration thatphysical findings provide useful information in patients witha common illness such as chronic heart failure may motivatephysicians and trainees to refine their diagnostic skills. Ourstudy tested the hypothesis that the finding of elevated jugularvenous pressure or a third heart sound (also called S3 gallop)on physical examination would provide important and independentprognostic information in patients with heart failure.
Methods
The Studies of Left Ventricular Dysfunction (SOLVD) treatmenttrial has been described in detail previously.8,9 A total of2569 patients with symptomatic congestive heart failure or ahistory of it and a left ventricular ejection fraction of 0.35or less were randomly assigned to receive enalapril or placebo.Patients were enrolled from June 1986 to March 1989. A prerandomizationrun-in phase consisted of a single-blind active-drug phase (2to 7 days) followed by a placebo run-in phase (14 to 17 days).Patients with worsening heart failure during this phase wereexcluded from the trial. Treatment was initiated predominantlyin the outpatient setting (in 99 percent of cases). The participantswere followed for an average (±SD) of 32±15 months.The study protocol was approved by the appropriate review boardsof the participating centers, and written informed consent wasobtained from the patients.
Data Collection and Definitions
Base-line demographic data including the New York Heart Association(NYHA) functional class and information on the medical historyand current use of medications were obtained from all patientsat the time of enrollment. Data on race and ethnic backgroundwere obtained from the SOLVD eligibility form, on which theethnic and racial categories were American Indian, Asian, black,white, Hispanic, and other. At the time of enrollment, investigatorsevaluated patients for the presence or absence of elevated jugularvenous pressure and a third heart sound on the basis of a routinephysical examination. On separate lines of the SOLVD base-linevisit form completed at the time of enrollment, the presenceof elevated jugular venous pressure or a third heart sound wasindicated in a "yes" or "no" format.
Definition of End Points
The primary end point of the SOLVD treatment trial was deathfrom any cause. The cause of death was also classified on standardforms after a review by the principal investigator at each centerof the circumstances surrounding each death. Deaths from cardiovascularcauses could be classified as due to pump failure, probablearrhythmia with some antecedent worsening of heart failure,or probable arrhythmia with no antecedent worsening of heartfailure. As previously described,10,11 in this study we classifiedall deaths attributed to pump failure and those attributed toprobable arrhythmia with some antecedent worsening of heartfailure as due to pump failure. Deaths due to probable arrhythmiawith no antecedent worsening of heart failure were classifiedas deaths from arrhythmia. The primary SOLVD investigator ateach center also classified the primary cause of hospitalization.As in a previous study,11 we prespecified that both death frompump failure and the composite end point of death from all causesor hospitalization for heart failure would represent progressionof heart failure.
Statistical Analysis
Patients with incomplete data were excluded from analysis, leaving2479 participants. The following variables were treated as continuous:age, left ventricular ejection fraction, systolic blood pressure,heart rate, serum creatinine level, and serum sodium level.Dichotomous variables included elevated jugular venous pressure(yes or no) or audible third heart sound (yes or no); blackrace (yes or no); cause of left ventricular systolic dysfunction(ischemic or nonischemic); NYHA functional class (I or II vs.III or IV); electrocardiographic evidence of atrial fibrillationat base line (yes or no); history of medical conditions (yesor no for each), including diabetes, hypertension, myocardialinfarction, and stroke; base-line use of medications at thetime of randomization (yes or no for each), including diuretics,beta-blockers, digoxin, and antiarrhythmic agents; and randomassignment to the enalapril group or the placebo group. We usedStudent's t-test to compare continuous data, assuming whereappropriate that the variance was unequal, and the chi-squarestatistic to compare binary data. We used Cox proportional-hazardmodels to assess the univariate and multivariate associationof independent variables with the outcome. The risk of an outcomeassociated with the presence of physical-examination findingswas assessed in three separate models, one for elevated jugularvenous pressure, one for a third heart sound, and one for elevatedjugular venous pressure or a third heart sound alone or in combination.We constructed two sets of Kaplan–Meier curves for thecomposite end point of death or hospitalization for heart failure,one according to the presence or absence of elevated jugularvenous pressure and one according to the presence or absenceof a third heart sound. We used the log-rank test to determineevent-free survival according to the presence or absence ofthese findings. A two-sided P value of less than 0.05 was consideredto indicate statistical significance in all analyses. The SOLVDdata base, which is held by the National Heart, Lung, and BloodInstitute, was acquired by the study investigators and independentlyanalyzed at the Donald W. Reynolds Cardiovascular Clinical ResearchCenter in Dallas.
Results
Base-Line Characteristics of the Patients
The base-line characteristics of the patients with either elevatedjugular venous pressure or a third heart sound are shown inTable 1. Patients with elevated jugular venous pressure andthose with a third heart sound had more advanced heart failurethan those without these physical findings, as assessed on thebasis of other measures of the severity of heart failure, includingNYHA functional class, left ventricular ejection fraction, andheart rate. Patients with elevated jugular venous pressure andthose with a third heart sound were also more likely to be womenand to have a nonischemic cause of left ventricular dysfunction.Patients with elevated jugular venous pressure were more likelythan those without elevated jugular venous pressure to haveatrial fibrillation and a history of diabetes and to be treatedwith diuretics. Patients with a third heart sound were lesslikely than those without a third heart sound to have a historyof myocardial infarction and to be treated with beta-blockers.Patients with elevated jugular venous pressure or a third heartsound and patients without these physical findings were equallylikely to be assigned to receive enalapril.
Table 1. Base-Line Characteristics of the Patients, According to the Presence or Absence of Elevated Jugular Venous Pressure and a Third Heart Sound.
Incidence of End Points
The incidence of death from all causes, hospitalization forheart failure, or a composite end point of death or hospitalizationfor heart failure is shown in Table 2 according to the presenceor absence of elevated jugular venous pressure and a third heartsound. In both cases, patients with these physical findingshad significantly increased rates of death, hospitalizationfor heart failure, the composite end point of death or hospitalizationfor heart failure, and death from pump failure, but not of deathfrom arrhythmia. The event-free survival curves are shown inFigure 1 according to the presence or absence of elevated jugularvenous pressure and a third heart sound.
Figure 1. Kaplan–Meier Analysis of Event-free Survival According to the Presence or Absence of Elevated Jugular Venous Pressure (Panel A) and a Third Heart Sound (Panel B).
The end point was a composite of death or hospitalization for heart failure. In Panel A, the 280 patients with elevated jugular venous pressure were significantly more likely than the 2199 patients without elevated jugular venous pressure to reach the composite end point (P<0.001 by the log-rank test). In Panel B, the 597 patients with a third heart sound were significantly more likely than the 1882 patients without a third heart sound to reach the composite end point (P<0.001 by the log-rank test).
Univariate Analysis
Univariate analysis showed that patients with elevated jugularvenous pressure were at significantly higher risk than patientswithout elevated jugular venous pressure for death from allcauses (relative risk, 1.52; 95 percent confidence interval,1.27 to 1.82; P<0.001), hospitalization for heart failure(relative risk, 1.78; 95 percent confidence interval, 1.47 to2.17; P<0.001), the composite end point of death or hospitalizationfor heart failure (relative risk, 1.69; 95 percent confidenceinterval, 1.45 to 1.97; P<0.001), and death from pump failure(relative risk, 1.99; 95 percent confidence interval, 1.57 to2.52; P<0.001), but not death from arrhythmia (relative risk,1.10; 95 percent confidence interval, 0.72 to 1.68; P=0.66).
The findings in patients with a third heart sound were similarto those in patients with elevated jugular venous pressure.On univariate analysis, patients with a third heart sound wereat significantly higher risk than those without a third heartsound for death from all causes (relative risk, 1.35; 95 percentconfidence interval, 1.17 to 1.55; P<0.001), hospitalizationfor heart failure (relative risk, 1.70; 95 percent confidenceinterval, 1.46 to 1.97; P<0.001), the composite end pointof death or hospitalization for heart failure (relative risk,1.42; 95 percent confidence interval, 1.26 to 1.60; P<0.001),and death from pump failure (relative risk, 1.77; 95 percentconfidence interval, 1.46 to 2.15; P<0.001), but not deathfrom arrhythmia (relative risk, 1.22; 95 percent confidenceinterval, 0.90 to 1.65; P=0.20).
Multivariate Analysis
Multivariate analysis showed that patients with elevated jugularvenous pressure and those with a third heart sound were at significantlyincreased risk for hospitalization for heart failure, the compositeend point of death or hospitalization for heart failure, anddeath from pump failure, but not death from arrhythmia (Table 3).
Of the 2479 patients, a total of 706 had elevated jugular venouspressure, a third heart sound, or both: 109 had elevated jugularvenous pressure in the absence of a third heart sound, 426 hada third heart sound in the absence of elevated jugular venouspressure, and 171 had both elevated jugular venous pressureand a third heart sound. Multivariate analysis with the useof the same covariates as described above showed that, as comparedwith the 1773 patients with neither finding, patients with elevatedjugular venous pressure, a third heart sound, or both were atsignificantly increased risk for death from all causes, hospitalizationfor heart failure, the composite end point of death or hospitalizationfor heart failure, and death from pump failure, but not deathfrom arrhythmia (Table 3). In addition, a multivariate analysisin which the 171 patients who had both elevated jugular venouspressure and a third heart sound were compared with the 535patients who had only one of these physical findings showedthat the risk of all outcomes, including hospitalization forheart failure (relative risk, 1.13; 95 percent confidence interval,0.86 to 1.48; P=0.38) and the composite end point of death orhospitalization for heart failure (relative risk, 1.05; 95 percentconfidence interval, 0.84 to 1.30; P=0.69), was similar.
Multivariate Analysis Stratified According to NYHA Functional Class and Treatment Assignment
In the light of the disparities at base line in the NYHA functionalclass between patients with and those without the physical findings,we performed a multivariate analysis that was stratified accordingto the NYHA class (1671 patients were in NYHA class I or IIand 808 were in NYHA class III or IV). With the exception ofthe NYHA functional class, the same covariates included in theprimary analysis were entered into these models. As shown inTable 4, the results of this subgroup analysis were consistentwith those of the primary analysis. In both NYHA class stratathe presence of elevated jugular venous pressure alone; a thirdheart sound alone; or elevated jugular venous pressure, a thirdheart sound, or both was associated with a relative risk ofmore than 1.00 in the case of hospitalization for heart failure,the composite end point of death or hospitalization for heartfailure, and death from pump failure, though not all valuesreached statistical significance.
Table 4. Results of the Multivariate Analysis Stratified According to the New York Heart Association (NYHA) Class and Treatment Assignment.
To determine whether treatment with angiotensin-converting–enzymeinhibitors altered the prognostic value of the physical-examinationfindings, we also performed a multivariate analysis that wasstratified according to treatment assignment. With the exceptionof treatment assignment, the same covariates included in theprimary analysis were entered into these models. As shown inTable 4, the presence of elevated jugular venous pressure alone;a third heart sound alone; or elevated jugular venous pressure,a third heart sound, or both was associated with similar risksfor most outcomes in the two treatment groups. In addition,there was no evidence of a statistically significant interactionbetween treatment assignment and elevated jugular venous pressureor between treatment assignment and a third heart sound withrespect to the risk of death, hospitalization for heart failure,the composite end point of death or hospitalization for heartfailure, and death from pump failure when these interactionterms were included in multivariate models (P>0.1 for allcomparisons).
Discussion
These data suggest that the finding of elevated jugular venouspressure or a third heart sound on physical examination conveysimportant prognostic information in patients with symptomaticheart failure. The presence of these signs was associated withsubsequent hospitalization for heart failure and an increasedrisk of progression of heart failure, as assessed by the incidenceof death from pump failure and the composite end point of deathor hospitalization for heart failure. The subgroup of patientswith elevated jugular venous pressure, a third heart sound,or both was also at increased risk for death from all causes.These associations persisted even after adjustment for manyother markers of the severity of heart failure, including theleft ventricular ejection fraction, the NYHA functional class,and the serum sodium level.
There are limited data regarding the prognostic value of thedetection of elevated jugular venous pressure on physical examinationin patients with heart failure.12 An increased right atrialpressure is associated with a poor prognosis in patients withheart failure.13,14 Such data may not be applicable to estimatesof jugular venous pressure obtained by physical examination,since the latter correlate poorly with findings derived frominvasive measurements of right atrial pressure.15,16,17,18,19,20Recent suggestions may improve the accuracy of the clinicalassessment of venous pressure.21 There is an association betweena finding of elevated jugular venous pressure on physical examinationand a finding of elevated left-sided filling pressures on rightheart catheterization in patients with heart failure.22,23,24,25A recent study of patients with a history of NYHA class IV symptomsshowed that a low congestion score, as assessed by a five-pointclinical scoring system that included one point for elevatedjugular venous pressure, was associated with a favorable outcome.26
Although the finding of a third heart sound is reported to bean unfavorable prognostic sign in patients with heart failure,27this association is based on relatively small observationalstudies.12,13,28,29,30,31 In addition, the majority of thesestudies did not adjust for other markers of the severity ofheart failure such as the left ventricular ejection fraction.In a study of 50 patients with advanced heart failure, nearlyall (96 percent) had a third heart sound,22 suggesting thatthis sign would have limited use as a discriminatory factor.Several studies have shown that the agreement between observerswith respect to the presence of a third heart sound is moderateor low32,33,34,35 even among experienced physicians, raisingserious questions about the usefulness of this sign.36 Suchfindings are probably representative of an overall decline incardiac auscultatory skills in physicians, as documented byassessments of recent medical school graduates.5,6 Our findingsnevertheless suggest that the detection of a third heart soundon physical examination is an important independent prognosticfactor in patients with heart failure.
Why elevated jugular venous pressure or a third heart soundwas associated with an increased risk of progressive heart failureis uncertain. Elevated jugular venous pressure reflects increasedright atrial pressure, which itself correlates with elevatedleft-sided filling pressures in patients with chronic heartfailure.37 Elevated left-sided filling pressures have been associatedwith adverse outcomes in patients with heart failure12,14,30,38,39possibly as a result of apoptosis40 due to myocardial stretchor enhanced activation of the sympathetic nervous system.41,42Patients with heart failure may have a third heart sound asa result of low ventricular compliance, increased filling pressures,or increased early diastolic filling rates.43,44,45,46 A similarcombination of pathophysiological events in diastole in patientswith left ventricular systolic dysfunction as assessed by echocardiography47,48 has been associated with an unfavorable prognosis.49,50,51
Our retrospective analysis has several important limitations.There may have been residual confounding by unmeasured and measuredvariables despite our efforts to adjust for known risk factorswith the use of multivariate modeling. The manner in which thephysical examination was performed to detect elevated jugularvenous pressure or a third heart sound was not standardizedin the SOLVD trials, although the approach was probably representativeof clinical practice. Physical examination has inherent inaccuracies,and no confirmatory test was performed (e.g., phonocardiographyfor a third heart sound), although any random misclassificationresulting from physicians' errors would bias the results towardthe null hypothesis. A physician's estimate of the overall severityof the patient's condition may have affected his or her assessmentof whether elevated jugular venous pressure or a third heartsound was present. However, such estimates of disease severitywould probably also affect the NYHA classification, and ourconclusions were based on multivariate models that adjustedfor the NYHA class. Furthermore, the findings of a subgroupanalysis stratified according to the NYHA class were consistentwith those of the primary analysis.
The decision to hospitalize a patient with heart failure mayhave been affected by the presence of either elevated jugularvenous pressure or a third heart sound. Such bias is unlikelyto explain the results of our study, since the findings of thephysical examination were noted at the time of enrollment andhospitalization for heart failure often occurred many monthslater, since the presence of a third heart sound by itself wouldprobably not be an indication for hospitalization, and sincethe presence of at least one of the physical-examination findingswas associated with an increased risk of death from all causesin addition to end points incorporating hospitalization. Theclassification of the cause of death as pump failure may alsohave been affected by the finding of elevated jugular venouspressure or a third heart sound near the time of death, althoughthese findings would often have been noted well after the base-linephysical examination had been performed.
Because of the infrequent use of beta-blockers in the SOLVDtrials, we could not determine whether beta-blockers affectthe prognostic value of the finding of elevated jugular venouspressure or a third heart sound. However, the multivariate modelsin this study did adjust for the use of beta-blockers. We alsodid not address the usefulness of the finding of elevated jugularvenous pressure or a third heart sound as an indicator of leftventricular systolic dysfunction25,52 since the entry criteriafor the SOLVD treatment trial included an ejection fractionof 0.35 or less.
In conclusion, the detection of elevated jugular venous pressureor a third heart sound in patients with heart failure was associatedwith adverse outcomes, including progression of heart failure,even after adjustment for other markers of the severity of disease.These findings may increase confidence in the belief that focusedbedside assessment is clinically meaningful and may give physiciansin training further impetus to refine their skills in physicalexamination.
Drs. Drazner, Rame, and Dries received support from the DonaldW. Reynolds Cardiovascular Clinical Research Center, Dallas.Dr. Drazner was a recipient of a Clinical Scientist DevelopmentAward from the Doris Duke Charitable Foundation. The SOLVD treatmenttrial was sponsored by the National Heart, Lung, and Blood Institute.Study drug and placebo were provided by Merck.
We are indebted to the investigators and coordinators involvedin the SOLVD treatment trial without whom this study would nothave been possible.
Source Information
From the Heart Failure Research Unit, Donald W. Reynolds Cardiovascular Clinical Research Center (M.H.D., J.E.R., D.L.D.), and the Division of Cardiology, Department of Internal Medicine (M.H.D., D.L.D.), University of Texas Southwestern Medical Center, Dallas; and the Cardiovascular Division, Brigham and Women's Hospital, Boston (L.W.S).
Address reprint requests to Dr. Drazner at UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9034, or at mark.drazner{at}utsouthwestern.edu.
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