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Corresponding Author: Joseph Mercy Ann Arbor Hospital, Department of Internal Medicine, Address: Suite 3009, Reichert Health Center, 5333 McAuley Dr, Ypsilanti, MI 48197, Phone: 1-734-712-5858,
St. Joseph Mercy Ann Arbor Hospital, Department of Internal Medicine, Address: Suite 3009, Reichert Health Center, 5333 McAuley Dr, Ypsilanti, MI 48197
St. Joseph Mercy Ann Arbor Hospital, Department of Internal Medicine, Address: Suite 3009, Reichert Health Center, 5333 McAuley Dr, Ypsilanti, MI 48197
St. Joseph Mercy Ann Arbor Hospital, Department of Internal Medicine, Address: Suite 3009, Reichert Health Center, 5333 McAuley Dr, Ypsilanti, MI 48197
St. Joseph Mercy Ann Arbor Hospital, Department of Internal Medicine, Address: Suite 3009, Reichert Health Center, 5333 McAuley Dr, Ypsilanti, MI 48197
St. Joseph Mercy Ann Arbor Hospital, Department of Internal Medicine, Address: Suite 3009, Reichert Health Center, 5333 McAuley Dr, Ypsilanti, MI 48197
Patients with obstruction to the left ventricular outflow tract from degenerative aortic stenosis (AS) usually do not become symptomatic until their disease becomes graded as severe. We sought to assess the accuracy of the physical examination for the diagnosis of AS of at least moderate severity.
Methods
A systematic review and meta-analysis of case series and cohorts of patients who received a cardiovascular physical examination prior to receiving a left heart catheterization or an echocardiogram.PubMed, Ovid Medline, the Cochrane Library, ClinicalTrials.gov, and Embase were searched form inception through December 10, 2021, without language restrictions.
Results
Our systematic review yielded seven observational studies with adequate data to perform a meta-analysis on three physical examination maneuvers. The presence of auscultating a diminished second heart sound (S2) (LR = 10.87, 95% CI, 3.94 – 30.12, P<.05) and palpating a delayed carotid upstroke (LR = 9.04, 95% CI, 3.12 -25.44, P<.05 are useful for detecting AS of at least moderate severity. The absence of a systolic murmur radiating to the neck, (LR = 0.11, 95% CI, 0.06 – 0.23, P<.05) rules against AS of at least moderate severity.
Conclusion
Low quality evidence from observational studies support a diminished S2 and a delayed carotid upstroke as having moderate accuracy in diagnosing the presence of AS of at least moderate severity, while the absence of a murmur radiating to the neck is equally accurate in excluding this diagnosis.
Degenerative valvular heart diseases such as aortic stenosis (AS) and mitral regurgitation are now much more common than rheumatic heart disease in many countries worldwide.
As valvular degeneration of the aortic valve leads to stenosis, the progressive increase in the obstruction to the left ventricular outflow tract can result in a decline in cardiac output, impaired exercise tolerance, and congestive heart failure (CHF).
2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
Journal of the American College of Cardiology.2014; 63: e57-185
The importance of clinical symptoms are paramount as they are the strongest marker of mortality in patients with AS, with a 50% two-year mortality without valve replacement with the development of syncope, chest pain or CHF.
Health JM. U.S. Aortic Stenosis Disease Prevalence & Treatment Statistics. https://www.johnmuirhealth.com/services/cardiovascular-services/intervention/transcatheter-aortic-valve-replacement/facts-and-figures.html. Published 2022. Accessed April 25, 2022.
Health JM. U.S. Aortic Stenosis Disease Prevalence & Treatment Statistics. https://www.johnmuirhealth.com/services/cardiovascular-services/intervention/transcatheter-aortic-valve-replacement/facts-and-figures.html. Published 2022. Accessed April 25, 2022.
The natural history of AS is one in which patients are generally unaware of their condition until they develop symptoms, which portends a four-fold increase in mortality.
Mounting evidence exists for the clinical benefit of early intervention in asymptomatic severe AS, emphasizing the importance of early and accurate detection.
Evaluation of the precordial impulse, cardiac auscultation, and characteristics of carotid impulse are longstanding approaches for diagnosing aortic stenosis using physical exam. With the rapid technological advances in the treatment of aortic stenosis combined with the curative nature of an aortic valve replacement (AVR), there is a clear importance of early and accurate detection of AS. Given the lack of evidence to support any benefit from medical treatment to alter the progression of AS, an approach to identify patients in need of a valve replacement could improve outcomes as well as costs. We performed our systematic review and meta-analysis to identify the most accurate physical examination findings for detection of AS of least moderate severity.
Methods
Protocol and registration
We have registered our systematic review and meta-analysis through PROSPERO (CRD42022312606). Our study is reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) Guideline.
Data sources, search strategy, study selection, and eligibility criteria
Our search strategies were established by using Medical subject heading (MESH) terms and text words and search terms which were selected based on common indexing practices and tested repeatedly to capture all potentially relevant studies. PubMed, Ovid Medline, the Cochrane Library, ClinicalTrials.gov, and Embase were searched by two authors (SC and RS) from inception through March 10, 2022, without language restrictions. Additional studies were found by author and reference tracking.
After removing duplicates, two investigators (SC and RS) screened titles and abstracts for eligibility criteria. Full text reviews were performed on studies which contained data on patients having a cardiac physical examination prior to having an echocardiogram or a left heart catheterization as the reference standard. Consensus was achieved for all phases of study selection and any disagreements were reconciled by discussion.
Inclusion criteria were prospective or retrospective observational studies in which patients received a cardiac physical examination prior to receiving diagnostic confirmation by using a reference standard imaging test. We accepted an echocardiogram as well as a left heart catheterization as a gold standard diagnostic imaging test for aortic stenosis. Exclusion criteria included: studies that did not record physical examination findings that were blinded to the results of the reference standard confirmatory diagnostic test; studies that did not confirm the physical examination with a reference standard; studies who did not report the number of patients in the study group or only reported in percentages or likelihood ratios.
Data extraction and Quality Assessment
Studies which met inclusion criteria were then selected for data extraction and statistical analysis. Study characteristics were identified and included: study description; patient demographics; percentage of patients with moderate and severe AS; physical examination maneuvers studied; and details of the reference standard confirmatory diagnostic test (Table 1). Two investigators independently assessed the quality and risk of bias of all included studies using the Newcastle-Ottawa Quality Assessment Tool for the Observational, Cohort and Cross-Sectional Studies available from the National Institute of Health.
Institute OHR. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonramdmised studies in meta-analysis, http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Published 2022. Accessed April 15, 2022.
The certainty of evidence was evaluated for each study by using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) assessment
Correlation of prevalence and severity of valvular aortic stenosis determined by continuous-wave Doppler echocardiography with physical signs of aortic stenosis in patients aged 62 to 100 years with aortic systolic ejection murmurs.
The American journal of cardiology.1987; 60: 399-401
Meta-analyses were performed when sufficient studies were available to pool sensitivities, specificities, and diagnostic odds ratios for each of the different measures. Table 1 outlines the study characteristics of the included studies for the four physical examination findings for which we have collected data. Meta-analyses of studies reporting sensitivity and specificity of diagnostic modalities generally employ bivariate methods that model both simultaneously. We have included Forest plots showing the values of these statistics for individual studies. Pooling of the results are illustrated using hierarchical summary receiver-operating characteristic curves (Supplemental Figure S1). Diagnostic odds ratios (DOR) are also presented using traditional univariate meta-analysis methods. Either the random effects or fixed effects pooling methods were employed, depending on the value of the I2 statistic. Outlier studies were deleted, and the analysis was revised when funnel plots suggested the potential for publication bias (Supplemental Figure S2). Analysis was performed using the meta and mada packages in R as well as the metandi (Habord & Whiting, 2009) module for Stata.
Doebler P. mada: Meta-Analysis of Diagnostic Accuracy. R package version 0.5.10. https://CRAN.R-project.org/package=mada. Published 2020. Accessed April 8, 2022.
This study did not receive any funding. The Institutional Review Board at Trinity Health Ann Arbor Hospital deemed this project to be exempt from ethical approval.
Results
After screening 3822 titles and abstracts, 44 studies were selected for full text review (Figure 1). Seven studies met inclusion criteria and had data extracted for statistical analysis from a total of 868 patients (Table 1).
Correlation of prevalence and severity of valvular aortic stenosis determined by continuous-wave Doppler echocardiography with physical signs of aortic stenosis in patients aged 62 to 100 years with aortic systolic ejection murmurs.
The American journal of cardiology.1987; 60: 399-401
Correlation of prevalence and severity of valvular aortic stenosis determined by continuous-wave Doppler echocardiography with physical signs of aortic stenosis in patients aged 62 to 100 years with aortic systolic ejection murmurs.
The American journal of cardiology.1987; 60: 399-401
The summary of pooled meta-analysis data for the delayed carotid upstroke in regard to sensitivity, specificity and LRs are reported in Table 2. Univariate analysis was conducted for DOR employing a random effects pooling method due to the moderate heterogeneity of studies. The pooled odds ratio based on all six studies is large and significant, 13.81 (95% CI, 6.85 - 27.83) (Figure 2). Two studies (Aronow, 1987
Correlation of prevalence and severity of valvular aortic stenosis determined by continuous-wave Doppler echocardiography with physical signs of aortic stenosis in patients aged 62 to 100 years with aortic systolic ejection murmurs.
The American journal of cardiology.1987; 60: 399-401
) were identified as having particularly large odds ratios and may be introducing publication bias. The analysis was performed without the outliers, and the remaining four studies still produced a large and significant pooled diagnostic odds ratio of 11.06 (95% CI, 5.62 - 21.75)(Table 2). We identified only one study reporting interobserver reliability for this physical examination finding, which was a kappa score of 0.26.
Correlation of prevalence and severity of valvular aortic stenosis determined by continuous-wave Doppler echocardiography with physical signs of aortic stenosis in patients aged 62 to 100 years with aortic systolic ejection murmurs.
The American journal of cardiology.1987; 60: 399-401
Pooled sensitivities, specificities, and likelihood ratios (LR) are reported in Table 2. There is also a moderate amount of heterogeneity between studies; therefore, DORs were calculated using the random effects pooling method. The pooled odds ratio is large and significant, 16.39 (95% CI, 7.85 - 34.20)(Figure 2). The funnel plot indicates the possibility of publication bias; therefore, the studies that generated the two largest odds ratios (Aronow, 1987
Correlation of prevalence and severity of valvular aortic stenosis determined by continuous-wave Doppler echocardiography with physical signs of aortic stenosis in patients aged 62 to 100 years with aortic systolic ejection murmurs.
The American journal of cardiology.1987; 60: 399-401
) were excluded and the pooled odds ratio for the remaining three studies was smaller but still significant (DOR = 11.86, 95% CI, 6.67 - 21.08). In searching for data on interobserver reliability for this physical sign, we found only one study which reported a kappa score of 0.54.
We report data from four studies with 662 patients which evaluated patients for the presence of a systolic murmur radiating to the neck for the diagnosis of aortic stenosis.
Correlation of prevalence and severity of valvular aortic stenosis determined by continuous-wave Doppler echocardiography with physical signs of aortic stenosis in patients aged 62 to 100 years with aortic systolic ejection murmurs.
The American journal of cardiology.1987; 60: 399-401
Once again, significant between-study variability exists. Unlike the prior two measures, whose specificities exceeded their sensitivities, murmur radiating to the neck is more sensitive and less specific (Table 2). There was minimal between-study heterogeneity and therefore the fixed effects model was employed. The pooled odds ratio was large and significant, (DOR = 23.03, 95% CI 12.08 - 43.92, P <.05)(Figure 2). The funnel plot did not reveal evidence of bias from large outliers; the study with low precision (Aronow, 1987
Correlation of prevalence and severity of valvular aortic stenosis determined by continuous-wave Doppler echocardiography with physical signs of aortic stenosis in patients aged 62 to 100 years with aortic systolic ejection murmurs.
The American journal of cardiology.1987; 60: 399-401
) reported the smallest odds ratio. We identified only one study which reported interobserver reliability of this physical examination sign, which was a kappa score of 0.33.
We found only two studies with 216 patients which we extracted data for a late peaking systolic ejection murmur in the diagnostic evaluation of aortic stenosis.
We chose to perform our systematic review and meta-analysis due to the importance of early detection of AS in an attempt to improve the unfavorable natural history of this degenerative valvular heart disease. To our knowledge, we are the first to perform a systematic review with a meta-analysis on the accuracy of the physical examination for the diagnosis of AS. Our study has identified three physical examination signs which are particularly useful in providing accuracy in the clinical bedside examination for the detection of aortic stenosis of moderate or greater severity. Two of the examination findings we studied have significantly positive LR, thus are accurate to help rule in the presence of AS. The diminished S2 was found to have an LR of 10.87 (95% CI, 3.94 – 30.12, P<.05) and palpating a delayed carotid upstroke had an LR of 9.04 (95% CI, 3.123 -25.435, P<.05)(Table 2). One physical examination finding was very good a discriminating against the diagnosis of AS, a systolic murmur radiating to the neck, which had a LR of 0.11 (95% CI, 0.056 – 0.232, P<.05)(Table 2). Thus, the absence of hearing a systolic murmur radiating to the neck is very accurate in helping to rule out AS. These data provide moderate support for the accuracy of the physical examination to diagnose AS of at least moderate severity. These interpretations of the use of LR are supported by McGee, who has explained a LR of 10 increased the probability by 45% of a disease or condition being present when a test or sign being positive or present, thus having a moderative positive predictive value.
Conversely an LR of 0.1 decreases the probability by 45% of a disease or condition being present in the absence of that test or sign, thus having moderate negative predictive value.
Our study was designed to identifying the most accurate physical examination maneuvers in evaluating patients with a systolic heart murmur in patients suspected of having AS. We fully recognize that several other physical signs should also be used when evaluating patients with systolic murmurs. Several physical signs which historically have been studied in the diagnosis of AS were identified in our systematic review; however, did not have enough data to be included in our meta-analysis. A palpable delay between the apical and carotid impulse has an excellent negative predictive value (LR of 0.05) in only one study.
A late peaking murmur has the best diagnostic evidence of any of the murmur characteristics which have been studied. Data from a small sample size from four studies revealed modest positive predictive value when this sign is present (LR of 3.7) as well as modest negative predictive value in its absence (LR = 0.2).
Correlation of prevalence and severity of valvular aortic stenosis determined by continuous-wave Doppler echocardiography with physical signs of aortic stenosis in patients aged 62 to 100 years with aortic systolic ejection murmurs.
The American journal of cardiology.1987; 60: 399-401
Correlation of prevalence and severity of valvular aortic stenosis determined by continuous-wave Doppler echocardiography with physical signs of aortic stenosis in patients aged 62 to 100 years with aortic systolic ejection murmurs.
The American journal of cardiology.1987; 60: 399-401
We believe our study has identified the most accurate physical examination findings which would be useful to include in the assessment of patients with systolic heart murmurs. Our systematic review and meta-analysis introduces data which to our knowledge, has not been presented elsewhere. Clinical implications for an accurate physical examination to enhance the early diagnosis of AS may include more expedient implementation of AVR which may decrease both disease burden and associated costs, and most importantly lead to lower morbidity and mortality.
There are several limitations to our study. We only identified eight studies which matched our eligibility criteria. In five of the studies, the sample size was less than 100, in the other three, the largest sample size was 231 (Table 1). Risk of bias was moderate to high in all the selected studies (Table 3). Selection bias was high as none of the studies had a control group for comparison and most of the case series or cohorts were comprised of patients with known AS. Independence between the findings of the physical examination and the results of the reference standard test occurred in four of the eight studies, which invites the possibility of bias in the reporting of outcomes.
There was only one study we identified which reported on the interobserver reliability on the three physical examination findings in our meta-analysis. We have identified age as a possible confounder for the physical finding of a delayed carotid upstroke as transmission velocity of the carotid pulse has shown to be higher in older compared with younger study subjects .
Since AS has a higher prevalence with increasing age, studies with age matched control patients without AS could shed more light on the effects of age on the carotid upstroke. There was moderate heterogeneity in the meta-analyses of the delayed carotid upstroke and the diminished intensity of S2, which means the results of the studies for these findings had a moderate degree of variability. The meta-analysis for murmur radiating to neck had low heterogeneity and was the best estimate of a true single effect size in our study. And finally, due to the nature of all our studies being observational the quality of evidence using the GRADE assessment is low.
Correlation of prevalence and severity of valvular aortic stenosis determined by continuous-wave Doppler echocardiography with physical signs of aortic stenosis in patients aged 62 to 100 years with aortic systolic ejection murmurs.
The American journal of cardiology.1987; 60: 399-401
In conclusion, our review of eight studies which included a total of 951 patients, we found low quality evidence for the physical examination findings for both positive and negative prediction for the presence and absence of aortic stenosis of at least moderate severity. The finding of a diminished S2 and a delayed carotid upstroke provide modest improvement in the pretest probability that a patient has moderate or greater severity aortic stenosis when evaluating systolic heart murmurs. The absence of a murmur radiating to the neck provides modest improvement on the post-test probability that a patient does not have at least moderate aortic stenosis. Further high-quality studies with control patients in carefully matched cohorts are necessary to shed more light on the accuracy of the physical examination in enhancing the early detection of aortic stenosis.
2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
Journal of the American College of Cardiology.2014; 63: e57-185
Health JM. U.S. Aortic Stenosis Disease Prevalence & Treatment Statistics. https://www.johnmuirhealth.com/services/cardiovascular-services/intervention/transcatheter-aortic-valve-replacement/facts-and-figures.html. Published 2022. Accessed April 25, 2022.
Institute OHR. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonramdmised studies in meta-analysis, http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Published 2022. Accessed April 15, 2022.
Doebler P. mada: Meta-Analysis of Diagnostic Accuracy. R package version 0.5.10. https://CRAN.R-project.org/package=mada. Published 2020. Accessed April 8, 2022.
Correlation of prevalence and severity of valvular aortic stenosis determined by continuous-wave Doppler echocardiography with physical signs of aortic stenosis in patients aged 62 to 100 years with aortic systolic ejection murmurs.
The American journal of cardiology.1987; 60: 399-401
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