Editor’s note: Go online to view the Journal Club questions in the Supplemental Digital Content: seehttp://links.lww.com/ESSR/A9.
The American Heart Association (AHA) and the American College of Cardiology (ACC) use a rigorous system for determining class recommendation and associated level of evidence for practice patterns, serving as the basis for their clinical guidelines. A detailed description of this system is provided elsewhere (21). The AHA/ACC has used this class recommendation/level of evidence system for the use of cardiopulmonary exercise testing (CPX) in patients with heart failure (HF). Initial guidance (1997 and 2002 update) afforded CPX a Class I recommendation (i.e., “conditions for which there is evidence or general agreement that a given procedure or treatment is useful and effective”) for the “evaluation of exercise capacity and response to therapy in patients with HF who are being considered for heart transplantation.” There was no associated level of evidence with this recommendation (19,20). The more recent HF-specific clinical guideline (2005 and 2009 update) changed the recommendation for CPX to Class IIa (i.e., “indicates that the weight of evidence/opinion is in favor of usefulness/efficacy”) as “being reasonable to identify high-risk patients presenting with HF who are candidates for cardiac transplantation or other advanced treatments” (32). The level of evidence associated with this recommendation was “B” (i.e., “a limited number of randomized controlled trials with small numbers of studies or observational registries”). No rationale was provided for the change in CPX class recommendation (i.e., from I to IIa).
Despite the change in class recommendation, CPX utilization in patients with HF has been viewed, at least in concept, as a widely available clinical standard of care for more than a decade (15). There are several caveats to previous CPX class recommendation and level of evidence designations that may not be readily apparent: 1) The reason CPX continues to be considered valuable in patients with HF who are being considered for heart transplantation or other advanced treatments is because of the assumption that this procedure provides a robust ability to predict adverse events, in particular, mortality. During the last decade, the value of CPX in predicting mortality in HF has been confirmed consistently by numerous observational studies, even in cohorts not being considered for transplantation or other advanced treatments. However, the view of the prognostic and, therefore, primary clinical utility of CPX remains narrowly focused on those being considered for end-stage interventions (e.g., transplantation); 2) In both previous AHA/ACC clinical practice guidelines and their revisions, peak oxygen consumption (V˙O2) was the only variable considered for the assessment of transplant candidacy, advanced treatments, or gauging therapeutic efficacy — despite the fact that a host of other potentially valuable CPX variables are readily obtainable; and 3) Given that heart transplantation continues to be reserved for patients diagnosed as having HF and reduced ejection fraction (HFrEF), the recommendations provided in these clinical guidelines were meant to apply exclusively to this subgroup. Thus, none of the CPX proposed recommendations provided in these guidelines apply to patients with HF and preserved ejection fraction (HFpEF). The body of scientific evidence and perceived clinical utility and value of CPX currently are incongruent. Stated succinctly, previous clinical practice guidelines perpetuate the following premise: Peak V˙O2 is the only CPX variable that holds prognostic value, only in patients with HFrEF. Scientific evidence, however, indicates that the value and clinical applications of CPX in the HF population are much richer and broader, respectively.
There have been many advances in the years since the 1997 and 2002 updates to the AHA/ACC Guidelines for Exercise Testing were published (19,20). The same can be said for the 2005 and 2009 updates to the guidelines for HF diagnosis and management (32). The clinical, pharmacologic, and surgical management of the HF population continues to expand and evolve, and, although prognosis in this chronic disease population remains disconcerting, it has improved substantially. Moreover, the unique pathophysiology, presentation, and clinical trajectory of patients diagnosed with HFrEF as compared with those with HFpEF are being recognized increasingly. Lastly, the body of evidence investigating the clinical utility of CPX with respect to prognostic, diagnostic, and therapeutic efficacy assessments continues to increase. As such, a new paradigm for CPX use and interpretation in HF is warranted. We hypothesize that scientific evidence for this new paradigm is substantial, proving that clinical utilization, class recommendations, and the associated level of evidence for CPX in the HF population can be expanded significantly.
Our group initiated a multicenter consortium in 2002 in an effort to gain better insights into the role of CPX in HF. Combining data from established centers allow important hypotheses to be tested with an appropriate sample size (currently n > 2500) and, thus, statistical power (36). The multicenter consortium has contributed significantly to the worldwide body of work related to CPX utility in HF (22). The collective body of available evidence supports the hypothesis that a new CPX paradigm is warranted, one that involves: 1) expanding the list of relevant CPX variables based on scientific evidence; 2) incorporating diagnostic, prognostic, and therapeutic efficacy applications; and 3) expanding utilization of CPX beyond patients with HFrEF being considered for heart transplantation.
Many of the studies discussed in subsequent sections of this article focus on results from the multicenter consortium, lending support to the hypothesis that a new CPX paradigm in HF is justifiable. Updated/revised/expanded class recommendations and associated levels of evidence will be presented with the following questions in mind: 1) Does CPX continue to provide prognostic value in patients with HF? 2) Would there be value to expanding the clinical applications of CPX to all patients with HF, as opposed to only those being evaluated actively for transplantation? 3) Should the list of CPX variables for prognostic assessment be expanded beyond peak V˙O2? 4) Are key CPX variables responsive to various interventions, allowing for a valid and reliable gauge of therapeutic efficacy? 5) What CPX variables(s) should be included in the assessment of therapeutic efficacy? 6) Are there diagnostic applications for CPX in patients with HF? and 7) Should CPX be used clinically in both the HFrEF and HFpEF populations?
CURRENT APPRAISAL OF THE PROGNOSTIC VALUE OF CPX
In 1991, Mancini et al. (34) published their seminal work on the predictive value of peak V˙O2 in a group of 114 patients with HFrEF, demonstrating its significant prognostic ability. Since that time and for reasons that are not clear, a narrow and limited clinical view of the prognostic value of CPX perpetuates, despite the fact that evidence continues to mount in support of a new broader paradigm.
The multicenter consortium has published a number of analyses related to the prognostic value of CPX, supporting the hypothesis that a new broader prognostic paradigm is warranted. The consortium’s work reaffirms the prognostic value of peak V˙O2 as well as significantly contributes to the rationale of expanding the prognostic assessment to other CPX variables based on sound physiologic rationale for why they may be relevant clinically. There is a specific interest in ventilatory efficiency, in particular, expressed as the minute ventilation per carbon dioxide production (VE/VCO2) slope. The multicenter consortium demonstrated that the VE/VCO2 slope portended an optimal prognostic value when all exercise testing data are used (i.e., from the initiation of the CPX to the attainment of maximal effort) (6), a finding subsequently supported by other research groups. A number of other consortium publications demonstrate that both the VE/VCO2 slope and peak V˙O2 are robust prognostic markers in patients with HFrEF (1,3,8,9,12). However, although both peak V˙O2 and the VE/VCO2 slope are significant prognostically, the latter is more robust in univariate analyses (3,7,8,16), a finding also supported by other research groups. However, both variables oftentimes remain significant prognostically in a multivariate model. In 2007, the consortium introduced a ventilatory classification system based on the VE/VCO2 slope (3). During the same period, the emergence of the beta-blocker era and its neutral impact on peak V˙O2 with a concomitant improvement in survival precipitated reconsideration of the less than or equal to/greater than 14 mLO2•kg−1•min−1 prognostic threshold. Indeed, a threshold of less than/greater than or equal to 10 mLO2•kg−1•min−1 was suggested to be more appropriate in HFrEF patients prescribed a beta-blocker (37). With respect to the VE/VCO2 slope, it seemed that patients with a value greater than or equal to 45 (normal value <30) had a particularly poor prognosis (3). As the body of literature evolved, it was proposed that patients with a VE/VCO2 slope greater than or equal to 45 and peak V˙O2 less than 10 mLO2•kg−1•min−1 had a particularly poor prognosis and should be considered to be at extremely high risk for adverse events (i.e., estimated to be >50%) (14). Moreover, for HFrEF patients with a VE/VCO2 slope and peak V˙O2 below and above these ominous thresholds, respectively, prognostic outlook improved progressively, with a multilevel model being the best approach to risk assessment. For patients with a VE/VCO2 slope less than 30 and peak V˙O2 greater than 20 mlO2•kg−1•min−1, prognosis is considered excellent, at least during the next 2 to 4 yr. This was the beginning of an expanded view of CPX variables for prognostic analysis and a new paradigm, combining the VE/VCO2 slope and the peak V˙O2 response.
Further growth of the multicenter HF consortium CPX database prompted exploration of the additive prognostic value of other CPX variables; both those obtained from ventilatory expired gas and traditional monitoring (i.e., heart rate, blood pressure, and subjective symptoms), further evolving the new paradigm. Exercise oscillatory ventilation (EOV) (26), the partial pressure of end-tidal CO2 (PETCO2) at rest and during exercise (10,13), heart rate recovery (HRR) (4,11), and dyspnea as a test termination criteria (18) are all prognostically significant in patients with HF, supporting the hypothesis that an expanding prognostic CPX paradigm portends an improved three-dimensional resolution in predicting adverse events. The demonstrated prognostic ability of all aforementioned CPX variables is grounded in the fact that each provides a unique reflection of the degree of pathophysiology present in one or more of the systems influencing the response to aerobic exercise (i.e., pulmonary/respiratory, cardiovascular, skeletal muscle). A discussion of the link between CPX measures and pathophysiology is beyond the scope of this article; other excellent resources addressing this issue are available (15). The multicenter consortium recently proposed a CPX score incorporating the majority of these variables (35), which was validated recently in a subsequent publication (36). Other research groups that have assessed large HF cohorts have demonstrated similar findings regarding the prognostic value of the aforementioned CPX variables.
In 2012, the AHA and European Association for Cardiovascular Prevention and Rehabilitation jointly published the Clinical Recommendations for Cardiopulmonary Exercise Testing Data Assessment for Specific Patient Populations, including HF (22). This joint statement recommends that the VE/VCO2 slope, peak V˙O2, EOV, PETCO2, systolic blood pressure response, exercise electrocardiography, HRR, and subjective symptom exercise termination criteria be assessed collectively for a more refined prognostic assessment. This color-coded prognostic model is illustrated in the Figure. This new paradigm represents the current best-practice recommendation for the interpretation of CPX data for prognostic purposes in the HF population. This new paradigm is supported strongly by evidence, reflecting a body of literature that collectively has assessed the prognostic value of CPX in thousands of patients with HF, with strong consistency in findings among the different research groups around the world. As such, we feel that the evidence-based model illustrated in the Figure is an excellent example of the vision for a new CPX paradigm that this article has set out to propose.
CPX AS A GAUGE FOR THERAPEUTIC EFFICACY
Although the original AHA/ACC Guidelines for Exercise Testing also afforded CPX a Class I recommendation to gauge the “response to therapy in patients with HF who are being considered for heart transplantation,” its use in this capacity is not commonplace clinically. This approach entails serial CPX testing before and after the implementation of a given intervention. Use of CPX as a gauge for therapeutic efficacy aligns with the prognostic applications previously described; if a given intervention improves the CPX response, it is reasonable to hypothesize that prognosis likewise improves. Given the robust prognostic value of CPX, in particular using the newly proposed multivariable paradigm illustrated in the Figure, assessing the change in key variables after the initiation or titration of a given intervention potentially would be of high value in guiding clinical management. The concept of serial CPX was reinforced in the 2007 multicenter consortium paper introducing the Ventilatory Classification System (3). Specifically, in patients with an abnormal VE/VCO2 slope, reviewing and titrating medical management are recommended. When medical management is titrated, repeating CPX to assess therapeutic efficacy is proposed. Other publications have demonstrated significant improvements in key CPX variables, most notably the VE/VCO2 slope and peak V˙O2, after numerous intervention strategies (23). Moreover, a reduction in pulmonary artery pressure after treatment with sildenafil, a phosphodiesterase 5 inhibitor, significantly correlates with the reduction in the VE/VCO2 slope (25). It also seems that treatment with sildenafil reverses EOV (31). In addition, an interleukin 1 receptor antagonist trial initially has demonstrated significant improvements in peak V˙O2 and the VE/VCO2 slope in patients with HFrEF after this pharmacologic intervention (38). These studies convincingly demonstrate that CPX is a valuable tool in indentifying responders versus nonresponders to a given therapeutic intervention, recalibrating prognostic outlook based on therapeutic responsiveness, and further titrating clinical management based on the level of responsiveness as reflected by the change in CPX. Physiologic mechanisms for the improvement in CPX variables are based uniquely on a specific therapeutic intervention (e.g., the reduction in the VE/VCO2 slope with sildenafil is related to the concomitant reduction in pulmonary pressure and subsequent improvement in ventilation-perfusion matching). In conclusion, the research findings described in this section support the premise that multiple CPX variables respond favorably to interventions that have a positive physiologic impact on the cardiovascular and/or pulmonary systems. Thus, assessing therapeutic CPX improvements through the new multivariate paradigm illustrated in the Figure is warranted.
THE DIAGNOSTIC APPLICATIONS OF CPX
The diagnostic applications of CPX in patients with HF previously have not been afforded a class recommendation and associated level of evidence designation in the AHA/ACC clinical practice guidelines. Admittedly, CPX as a tool to determine an initial diagnosis of HF would not be warranted because a number of other chronic conditions produce similar CPX abnormalities (e.g., pulmonary arterial hypertension, congenital heart defects, and interstitial lung disease). However, the use of CPX to aid in the diagnosis of secondary pathophysiologic consequences of HF seems appropriate and clinically valuable, in particular, left-sided pulmonary hypertension (PH) (28). Ventilatory inefficiency, as expressed by an elevated VE/VCO2 slope, possesses the ability to diagnose left-sided PH noninvasively with acceptable sensitivity/specificity and positive/negative predictive values. The pathophysiologic rationale for this relationship is the fact that increased pulmonary pressure creates a greater ventilation-perfusion mismatch, reflected by an elevated VE/VCO2 slope. Moreover, there seems to be a significant correlation between the severity of PH (i.e., degree of rise in pulmonary artery pressure) and the degree of elevation in the VE/VCO2 slope; thus, the latter seems to provide a noninvasive reflection of disease severity. As described in the review by Arena et al. (2), the majority of the literature supporting this premise has been performed in cohorts diagnosed as having primary pulmonary vascular disease. However, Guazzi et al. recently demonstrated that the VE/VCO2 slope (threshold </≥36, odds ratio = 12.1, P < 0.001) was the strongest predictor of an elevated pulmonary artery systolic pressure (≥40 mmHg), assessed by Doppler echocardiography, in an HF cohort (n = 293). Peak exercise PETCO2 (threshold ≤/>36 mmHg, odds ratio = 3.8, P < 0.001) and EOV (yes vs. no, odds ratio = 3.2, P < 0.001), CPX variables that also reflect ventilatory inefficiency, improved the ability to detect an elevated pulmonary artery systolic pressure (odds ratio for all three variables combined = 16.7, P < 0.001). Thus, although CPX is not viewed as an assessment that holds value in confirming an HF diagnosis, it does hold value in diagnosing secondary consequences of HF, namely, left-sided PH. Moreover, although CPX is valuable in accurately detecting left-sided PH, the authors of this review do not recommend it should be viewed as the test that would confirm such a diagnosis. Rather, if the CPX response is strongly suggestive of left-sided PH in patients with HF (i.e., indicators of ventilatory efficiency), an appropriate next step would be to consider a follow-up assessment to confirm the initial impression, such as Doppler echocardiography or right heart catheterization.
UNIQUE CONSIDERATIONS FOR THE APPLICATION OF CPX IN HF
As discussed in the Introduction, a primary and currently underexamined issue related to this focus is exploring the clinical value of CPX in patients diagnosed as having HFpEF. The multicenter consortium has examined the value of CPX in patients diagnosed as having HFpEF, supporting key facets of the newly proposed paradigm by demonstrating 1) a significant correlation between key CPX variables (i.e., peak V˙O2, the VE/VCO2 slope, resting and exercise PETCO2) and diastolic dysfunction, as assessed by Doppler echocardiography (i.e., E/E′) (24); and 2) the prognostic significance of the VE/VCO2 slope and EOV in patients with HFpEF (29,30). The multicenter consortium also has addressed other unique considerations in the CPX-HF literature, demonstrating 1) an interplay between the obesity paradox and the preserved prognostic value of peak V˙O2 and the VE/VCO2 slope (17,33); 2) the preserved prognostic value of CPX irrespective of both sex (27) and HF etiology (12); and 3) a 2- to 4-yr window for the prognostic validity of peak V˙O2 and the VE/VCO2 slope, after which time a repeat assessment may be warranted (5).
CPX CLASS RECOMMENDATIONS AND ASSOCIATED LEVELS OF EVIDENCE
It has been several years since the AHA/ACC class recommendations and associated levels of evidence have been reviewed for CPX in HF. Initially, CPX was afforded a Class I recommendation with no associated level of evidence in the AHA/ACC Guidelines for Exercise Testing (19). Moreover, the scope of the recommendation was rather narrow with respect to CPX variables assessed and the type of HF patients undergoing CPX (i.e., heart transplant candidates and HFrEF). The 2005 guidelines for the diagnosis and management of HF in adults revisited recommendations for CPX; changing the recommendation to Class IIa with an associated “B” level of evidence. To our knowledge, no rationale, evidence based or otherwise, was provided for this change in recommendation class. During this same time, the body of CPX literature has expanded exponentially, warranting reexamination of this issue. Our current assessment of this area allowed for several key observations to be made as a part of our newly proposed paradigm: 1) The AHA/ACC Class Recommendation/Level of Evidence System does not have language that describes specifically how to provide recommendations for or rate levels of evidence related to prognostic assessments; 2) The CPX body of literature in HF has expanded to a point where a more refined and detailed approach to class recommendation and associated level of evidence is justified. These observations serve as the genesis of the new conceptual framework provided in Tables 1 to 3. Tables 1 and 2 provide guidance on class recommendation and levels of evidence language and concepts. These tables are constructed with the intent of being applicable to all areas relevant to CPX (i.e., prognosis, therapeutic efficacy, and diagnosis). The language and concepts presented in Tables 1 and 2 form the basis for the proposed CPX class recommendations and associated levels of evidence for prognostic, therapeutic efficacy, and diagnostic applications in the HF population, which are listed in Table 3. Based on the body of literature, the number of CPX variables that should be considered, the variation in how extensively each individual variable has been studied currently, and the number of potential CPX indications in the clinical and research settings, a more refined and extensive list of class recommendations and levels of evidence is warranted. With respect to prognosis, peak V˙O2, the VE/VCO2 slope, and EOV are primary CPX markers with clear predictive values. Other variables add predictive values, and thus, a multivariate predictive model is appropriate. These recommendations are well established in patients with HFrEF. Initial prognostic analyses of CPX in patients with HFpEF shows promise but is more guarded, given that more research is needed in this area. The VE/VCO2 slope and peak V˙O2 are primary variables for gauging therapeutic efficacy, a premise well supported by the literature in patients with HFrEF. There also are some indications that reversal of EOV may occur with certain therapeutic interventions in patients with HFrEF, highlighting the important role this prognostic marker seems to have in clinical practice. In general, however, the use of CPX to gauge therapeutic efficacy in patients with HFpEF needs further inquiry. Lastly, the diagnostic utility of CPX may be useful in the overall HF population, in particular, the ability of abnormalities in ventilatory efficiency to detect left-sided PH. Additional research is needed to solidify the diagnostic value of CPX in HF.
The current concept paper set out to test the hypothesis that a new and expanded paradigm for CPX application and interpretation in HF is warranted. The current body of research, significantly contributing to by the multicenter consortium, supports this paradigm. Clinical guidelines published by the AHA/ACC have provided guidance on class recommendations and levels of evidence for CPX in patients with HF in a narrowly focused fashion. Given the new CPX paradigm proposed that is supported strongly by research in this article, revision to and expansion of class recommendations and associated levels of evidence is warranted. It is clear that several application-specific class recommendations and associated levels of evidence are appropriate. The authors propose that a primary prognostic recommendation for CPX be restored to a Class I recommendation at a level of evidence “A” for three primary variables in patients with HFrEF: 1) The VE/VCO2 slope, 2) EOV, and 3) peak V˙O2. The body of evidence clearly justifies this recommendation. There are numerous other indications and considerations for CPX that expand its utility. It is our hope that the CPX paradigm proposed herein, supported by a robust evidence base, increases appropriate utilization of this exercise assessment, improves patient care, and stimulates the future research needed to revise several of the newly proposed class recommendations and associated levels of evidence more definitively.
The authors acknowledge the significant contributions to the body of literature pertaining to CPX in HF that could not be cited because of reference limitations.
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