Guiding heart failure care by invasive hemodynamic measurements: Possible or useful?

Abstract

The quest to discover effective methodologies to monitor the course of disease and response to therapeutic agents in patients with chronic heart failure continues. The relentless progression of underlying left ventricular dysfunction and periodic, severe symptomatic decompensation often requiring hospitalization remain essential features of the heart failure syndrome despite significant therapeutic advances. Clinical trials of specific therapeutic agents have shown efficacy in large groups of patients. But outcome, even with the most effective agents, is recognized to be heterogeneous for largely unexplained reasons. The idea that treatment of individual patients with heart failure could be guided by serial measurements of surrogate end points for mortality and morbidity remains attractive to clinicians.Several assumptions underlie the concept that sequential physiologic measurements such as hemodynamics can be used to guide therapy: (1) measurements indicative of clinical response during heart failure can be ascertained, albeit with varying degrees of difficulty; (2) serial determinations of these measurements, such as left ventricular dysfunction, neurohormonal activation, and central hemodynamics, will predict clinical responses to general measures and pharmacologic therapy; (3) these measurements are not sufficiently risky, expensive, or cumbersome to preclude their being obtained as a part of routine clinical practice; (4) these measurements are sufficiently reproducible to provide the basis for making therapeutic changes in individual patients; (5) continuous measurements rather than serial snapshots of, for example, hemodynamics are likely best; (6) adjustment of currently available treatment strategies will favorably effect the measures that are monitored; (7) the frequency of therapeutic adjustments and subsequent follow-up study prompted by serial measurements is feasible for most patients; and (8) monitoring physiologic aspects of the disease process will provide more benefit than expending similar resources on changes in the process of delivery of care, ie, measurements of right heart hemodynamics with medication adjustment versus patient management via a heart failure program. Magalski et al1Magalski A Adamson P Gadler F Böehm M Steinhaus D Reynolds D Vlach K Linde C Cremers B Sparks B Bennett T Continuous ambulatory righ heart pressure measurements with an implantable hemodynamic monitor: a multicenter, 12-month follow-up study of patients with chronic heart failure.J Card Fail. 2002; 8: 63-70Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar in this issue of Journal of Cardiac Failure describe one strategy for monitoring the course of chronic heart failure that begins early work to address some of these issues.Study findingsMagalski et al1Magalski A Adamson P Gadler F Böehm M Steinhaus D Reynolds D Vlach K Linde C Cremers B Sparks B Bennett T Continuous ambulatory righ heart pressure measurements with an implantable hemodynamic monitor: a multicenter, 12-month follow-up study of patients with chronic heart failure.J Card Fail. 2002; 8: 63-70Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar report results on the potential of an implantable hemodynamic monitoring device (Chronicle IHM; Medtronic, Minneapolis, MN) to provide continuous measurements of central hemodynamics in patients with chronic heart failure. Their results confirm and extend previous work with implantable hemodynamic monitoring.2Ohlsson A Kubo SH Steinhaus D Connelly DT Adler S Bitkover C Nordlander R Ryden L Bennett T Continuous ambulatory monitoring of absolute right ventricular pressure and mixed venous oxygen saturation in patients with heart failure using an implantable hemodynamic monitor: results of a 1-year multicenter feasibility study.Eur Heart J. 2001; 22: 942-954Crossref PubMed Scopus (73) Google Scholar The investigators show that this approach is feasible in patients with severe heart failure and that accurate long-term monitoring is possible. A good correlation was found with little difference in group mean values between measurements obtained by the implantable device and standard fluid-filled catheters both at rest and during maneuvers designed to produce acute changes in hemodynamics. These findings are encour-aging but there may be some limitations concerning the application of measurements from the implantable device to specific patients. Substantial variations, likely to be of clinical importance, were noted for individual determinations of hemodynamic measures. Variation was more evident in the estimation of filling pressure with differences of 10 mm Hg between catheter and device measurements expected with some frequency, and the errors involved both overestimation and underestimation. Conceivably, a favorable impact of therapeutic adjustments can be seen in groups of patients despite this degree of variation. The key issue may turn on safety. Treatments based on measurements with this degree of variation may result in symptomatic hypotension or adverse shifts in fluid balance in enough patients to cause concern despite an overall beneficial effect in a group of patients. Clearly there are many ways to evaluate the large amount of data provided by the device; summary data may be of more benefit than very brief snapshots. Only results of randomized, controlled, and blinded clinical trials investigating interventions based on various strategies for using results from the device can adequately resolve this issue.Monitoring chronic heart failure therapyReview of available data on the ability of hemodynamic measurements to predict outcomes in patients with heart failure reveals conflicting results. Some studies suggest that hemodynamic parameters at rest or during exercise are significant independent predictors of out-come.3Metra M Faggiano P D'Aloia A Nodari S Gualeni A Raccagni D Dei Cas L Use of cardiopulmonary exercise testing with hemodynamic monitoring in the prognostic assessment of ambulatory patients with chronic heart failure.J Am Coll Cardiol. 1999; 33: 943-950Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar, 4Butler J Chromsky DB Wilson JR Pulmonary hypertension and exercise intolerance in patients with heart failure.J Am Coll Cardiol. 1999; 34: 1802-1806Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar Newer markers such as transpulmonary passage of albumin or findings on echo Doppler that approximate changes in estimated filling pressure may be helpful as markers of risk.5Sherman HL Avelar E Grossman PM Sachdev V Oral H Nicklas JM Armstrong WF Transpulmonary passage of Albunex as a marker of intracardiac hemodynamics and outcome in chronic congestive heart failure.Am Heart J. 2000; 139: 782-787Abstract Full Text PDF PubMed Scopus (7) Google Scholar, 6Martins S Soares RM Branco L Salomao S Antunes AM Noninvasive monitoring of pulmonary capillary wedge pressure in heart failure.Eur J Heart Fail. 2001; 3: 41-46Crossref PubMed Scopus (5) Google Scholar However, analysis of results from the FIRST trial of patients with advanced heart failure suggested that exercise capacity as assessed by the 6-minute walk test, not resting hemodynamic measurements, was predictive of outcome.7Adams K Sueta CA Califf RM Gheorgiade M Harrell F Uretsky B Swedberg K McKenna W Soler-Soler J Tomasko L Gender differences in survival in patients with advanced heart failure.Circulation. 1999; 99: 1816-1821Crossref PubMed Google Scholar, 8Shah MR Hasselblad V Gheorghiade M Adams KF Swedberg K Califf RM O'Connor CM Prognostic usefulness of the six-minute walk in patients with advanced congestive heart failure secondary to ischemic or nonis-chemic cardiomyopathy.Am J Cardiol. 2001; 88: 987-993Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar Even if a single snapshot of hemodynamics is not very predictive, other data suggest that serial changes in ejection fraction and peak oxygen consumption during exercise testing may be of greater value.9Florea VG Henein MY Anker SD Francis DP Chambers JS Ponikowski P Coats AJ Prognostic value of changes over time in exercise capacity and echocardiographic measurements in patients with chronic heart failure.Eur Heart J. 2000; 21: 146-153Crossref PubMed Scopus (72) Google ScholarData on the relationship between drug-induced changes in hemodynamics and outcomes are of particular interest. Angiotensin-converting enzyme inhibitor therapy produces sustained hemodynamic improvement, but early on a dissociation was observed between acute hemodynamic benefit and subsequent clinical outcomes.10Sharma S Deitchman D Eni JS Gelperin K Ilgenfritz JP Blumenthal M The hemodynamic effects of long-term ACE inhibition with fosinopril in patients with heart failure: Fosinopril Hemodynamics Study Group.Am J Ther. 1999; 6: 181-189Crossref PubMed Scopus (8) Google Scholar, 11Massie BM Kramer BL Topic N Lack of relationship between the short-term hemodynamic effects of captopril and subsequent clinical responses.Circulation. 1984; 69: 1135-1141Crossref PubMed Scopus (90) Google Scholar In contrast, hemodynamic response correlated better with drugs that had direct hemodynamic effects.12Massie B Ports T Chatterjee K Parmley W Ostland J O'Young J Haughom F Long-term vasodilator therapy for heart failure: clinical response and its relationship to hemodynamic measurements.Circulation. 1981; 63: 269-278Crossref PubMed Scopus (147) Google Scholar Interestingly, acute drug-induced changes in degree of pulmonary hypertension did not predict out-come in a group of high-risk patients undergoing evaluation for cardiac transplantation.13Levine TB Levine AB Goldberg AD Tobes AC Narins B Goldstein S Lesch M Acute reversibility of pulmonary hypertension predicts neither long-term hemodynamic response nor outcome in patients awaiting heart transplantation.Am J Cardiol. 1997; 79: 105-106Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar Other uncontrolled studies suggest that short-term success with “tailored” therapy with various medications in patients with severe heart failure is associated with a better outcome than inability to achieve hemodynamic targets.14Stevenson LW Tailored therapy before transplantation for treatment of advanced heart failure: effective use of vasodilators and diuretics.J Heart Lung Transplant. 1991; 10: 468-476PubMed Google Scholar, 15Stevenson LW Tillisch JH Hamilton M Luu M Chelimsky-Fallick C Moriguchi J Kobashigawa J Walden J Importance of hemodynamic response to therapy in predicting survival with ejection fraction less than or equal to 20% secondary to ischemic or nonis-chemic dilated cardiomyopathy.Am J Cardiol. 1990; 66: 1348-1354Abstract Full Text PDF PubMed Scopus (295) Google Scholar, 16Drazner MH Solomon MA Thompson B Yancy CW Tailored therapy using dobutamine and nitroglycerin in advanced heart failure.Am J Cardiol. 1999; 84: 941-943Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar Continued uncertainty over this approach, mainly because of the potential for selection of lower-risk patients based on favorable treatment response, led to the ESCAPE study. This trial will attempt to validate the tailored therapy approach in a prospective randomized controlled trial.17Shah MR O'Connor CM Sopko G Hasselblad V Califf RM Stevenson LW Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE): design and rationale.Am Heart J. 2001; 141: 528-535Abstract Full Text Full Text PDF PubMed Scopus (90) Google ScholarData on the relationship between outcomes and serial hemodynamic changes during drug therapy for heart failure are minimal. Despite concerns about the safety and efficacy of long-term administration of inotropic agents, recent data from an uncontrolled study of repeated administration of milrinone over several weeks in patients with end-stage heart failure showed sustained improvement in hemodynamics over 4-month follow-up.18Hatzizacharias A Makris T Krespi P Triposkiadis F Voyatzi P Dalianis N Kyriakidis M Intermittent milrinone effect on long-term hemodynamic profile in patients with severe congestive heart failure.Am Heart J. 1999; 138: 241-246Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar These findings again point to the complexity of predicting clinical benefit from pharmacologic interventions based on assessment of surrogate end points like hemodynamics.Although direct hemodynamic monitoring to improve the care of patients with chronic heart failure is intrinsically attractive, many studies suggest that other less invasive strategies are useful. Early results suggest that measurement of brain natriuretic peptide, now available as a point-of-care assay, is useful in identification of left ventricular dysfunction and may also predict adverse events during hospitalization and after discharge.19Maisel AS Practical approaches to treating patients with acute decompensated heart failure.J Card Fail. 2001; 7: 13-17Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar, 20Kazanegra R Cheng V Garcia A Krishnaswamy P Gardetto N Clopton P Maisel A A rapid test for B-type natriuretic peptide correlates with falling wedge pressures in patients treated for decompensated heart failure: a pilot study.J Card Fail. 2001; 7: 21-29Abstract Full Text Full Text PDF PubMed Scopus (389) Google Scholar Studies to determine if serial measurements of this neurohormone are useful should help in guiding the long-term management of patients with heart failure. Even less technical interventions involving disease management teams, the addition of a pharmacist or home monitoring by various means, may produce substantial improvement in morbidity.21Gattis WA Hasselblad V Whellan DJ O'Connor CM Reduction in heart failure events by the addition of a clinical pharmacist to the heart failure management team: results of the Pharmacist in Heart Failure Assessment Recommendation and Monitoring (PHARM) Study.Arch Intern Med. 1999; 159: 1939-1945Crossref PubMed Scopus (404) Google Scholar, 22De Lusignan S Wells S Johnson P Meredith K Leatham E Compliance and effectiveness of 1 year's home telemonitoring: the report of a pilot study of patients with chronic heart failure.Eur J Heart Fail. 2001; 3: 723-730Crossref PubMed Scopus (156) Google Scholar, 23Jerant AF Azari R Nesbitt TS Reducing the cost of frequent hospital admissions for congestive heart failure: a randomized trial of a home telecare intervention.Med Care. 2001; 39: 1234-1245Crossref PubMed Scopus (252) Google Scholar, 24Heidenreich PA Ruggerio CM Massie BM Effect of a home monitoring system on hospitalization and resource use for patients with heart failure.Am Heart J. 1999; 138: 633-640Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar, 25Constantini O Huck K Carlson MD Boyd K Buchter CM Raiz P Cooper GS Impact of a guideline-based disease management team on outcomes of hospitalized patients with congestive heart failure.Arch Intern Med. 2001; 161: 177-182Crossref PubMed Scopus (66) Google Scholar These findings bring into question what intervention is the most appropriate control for randomized trials attempting to show the efficacy of any serial physiologic measurement of chronic heart failure, hemodynamic or other. The strategy in the control group may be particularly important for morbidity end points such as rehospitalization in which disease management programs and even simple changes in process seem to have significant benefits.Although the points above emphasize the difficulty of developing effective strategies to guide management in chronic heart failure, they do not detract from the critical importance of this effort. Both from a clinical and economic standpoint, heart failure remains a major public health problem. Establishing a reliable method to optimize outcomes by monitoring treatment response would represent a major clinical advance. Careful consideration of measurements to make, end points to assess, and therapy in control patients will be essential to validate new approaches. The quest to discover effective methodologies to monitor the course of disease and response to therapeutic agents in patients with chronic heart failure continues. The relentless progression of underlying left ventricular dysfunction and periodic, severe symptomatic decompensation often requiring hospitalization remain essential features of the heart failure syndrome despite significant therapeutic advances. Clinical trials of specific therapeutic agents have shown efficacy in large groups of patients. But outcome, even with the most effective agents, is recognized to be heterogeneous for largely unexplained reasons. The idea that treatment of individual patients with heart failure could be guided by serial measurements of surrogate end points for mortality and morbidity remains attractive to clinicians. Several assumptions underlie the concept that sequential physiologic measurements such as hemodynamics can be used to guide therapy: (1) measurements indicative of clinical response during heart failure can be ascertained, albeit with varying degrees of difficulty; (2) serial determinations of these measurements, such as left ventricular dysfunction, neurohormonal activation, and central hemodynamics, will predict clinical responses to general measures and pharmacologic therapy; (3) these measurements are not sufficiently risky, expensive, or cumbersome to preclude their being obtained as a part of routine clinical practice; (4) these measurements are sufficiently reproducible to provide the basis for making therapeutic changes in individual patients; (5) continuous measurements rather than serial snapshots of, for example, hemodynamics are likely best; (6) adjustment of currently available treatment strategies will favorably effect the measures that are monitored; (7) the frequency of therapeutic adjustments and subsequent follow-up study prompted by serial measurements is feasible for most patients; and (8) monitoring physiologic aspects of the disease process will provide more benefit than expending similar resources on changes in the process of delivery of care, ie, measurements of right heart hemodynamics with medication adjustment versus patient management via a heart failure program. Magalski et al1Magalski A Adamson P Gadler F Böehm M Steinhaus D Reynolds D Vlach K Linde C Cremers B Sparks B Bennett T Continuous ambulatory righ heart pressure measurements with an implantable hemodynamic monitor: a multicenter, 12-month follow-up study of patients with chronic heart failure.J Card Fail. 2002; 8: 63-70Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar in this issue of Journal of Cardiac Failure describe one strategy for monitoring the course of chronic heart failure that begins early work to address some of these issues. Study findingsMagalski et al1Magalski A Adamson P Gadler F Böehm M Steinhaus D Reynolds D Vlach K Linde C Cremers B Sparks B Bennett T Continuous ambulatory righ heart pressure measurements with an implantable hemodynamic monitor: a multicenter, 12-month follow-up study of patients with chronic heart failure.J Card Fail. 2002; 8: 63-70Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar report results on the potential of an implantable hemodynamic monitoring device (Chronicle IHM; Medtronic, Minneapolis, MN) to provide continuous measurements of central hemodynamics in patients with chronic heart failure. Their results confirm and extend previous work with implantable hemodynamic monitoring.2Ohlsson A Kubo SH Steinhaus D Connelly DT Adler S Bitkover C Nordlander R Ryden L Bennett T Continuous ambulatory monitoring of absolute right ventricular pressure and mixed venous oxygen saturation in patients with heart failure using an implantable hemodynamic monitor: results of a 1-year multicenter feasibility study.Eur Heart J. 2001; 22: 942-954Crossref PubMed Scopus (73) Google Scholar The investigators show that this approach is feasible in patients with severe heart failure and that accurate long-term monitoring is possible. A good correlation was found with little difference in group mean values between measurements obtained by the implantable device and standard fluid-filled catheters both at rest and during maneuvers designed to produce acute changes in hemodynamics. These findings are encour-aging but there may be some limitations concerning the application of measurements from the implantable device to specific patients. Substantial variations, likely to be of clinical importance, were noted for individual determinations of hemodynamic measures. Variation was more evident in the estimation of filling pressure with differences of 10 mm Hg between catheter and device measurements expected with some frequency, and the errors involved both overestimation and underestimation. Conceivably, a favorable impact of therapeutic adjustments can be seen in groups of patients despite this degree of variation. The key issue may turn on safety. Treatments based on measurements with this degree of variation may result in symptomatic hypotension or adverse shifts in fluid balance in enough patients to cause concern despite an overall beneficial effect in a group of patients. Clearly there are many ways to evaluate the large amount of data provided by the device; summary data may be of more benefit than very brief snapshots. Only results of randomized, controlled, and blinded clinical trials investigating interventions based on various strategies for using results from the device can adequately resolve this issue. Magalski et al1Magalski A Adamson P Gadler F Böehm M Steinhaus D Reynolds D Vlach K Linde C Cremers B Sparks B Bennett T Continuous ambulatory righ heart pressure measurements with an implantable hemodynamic monitor: a multicenter, 12-month follow-up study of patients with chronic heart failure.J Card Fail. 2002; 8: 63-70Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar report results on the potential of an implantable hemodynamic monitoring device (Chronicle IHM; Medtronic, Minneapolis, MN) to provide continuous measurements of central hemodynamics in patients with chronic heart failure. Their results confirm and extend previous work with implantable hemodynamic monitoring.2Ohlsson A Kubo SH Steinhaus D Connelly DT Adler S Bitkover C Nordlander R Ryden L Bennett T Continuous ambulatory monitoring of absolute right ventricular pressure and mixed venous oxygen saturation in patients with heart failure using an implantable hemodynamic monitor: results of a 1-year multicenter feasibility study.Eur Heart J. 2001; 22: 942-954Crossref PubMed Scopus (73) Google Scholar The investigators show that this approach is feasible in patients with severe heart failure and that accurate long-term monitoring is possible. A good correlation was found with little difference in group mean values between measurements obtained by the implantable device and standard fluid-filled catheters both at rest and during maneuvers designed to produce acute changes in hemodynamics. These findings are encour-aging but there may be some limitations concerning the application of measurements from the implantable device to specific patients. Substantial variations, likely to be of clinical importance, were noted for individual determinations of hemodynamic measures. Variation was more evident in the estimation of filling pressure with differences of 10 mm Hg between catheter and device measurements expected with some frequency, and the errors involved both overestimation and underestimation. Conceivably, a favorable impact of therapeutic adjustments can be seen in groups of patients despite this degree of variation. The key issue may turn on safety. Treatments based on measurements with this degree of variation may result in symptomatic hypotension or adverse shifts in fluid balance in enough patients to cause concern despite an overall beneficial effect in a group of patients. Clearly there are many ways to evaluate the large amount of data provided by the device; summary data may be of more benefit than very brief snapshots. Only results of randomized, controlled, and blinded clinical trials investigating interventions based on various strategies for using results from the device can adequately resolve this issue. Monitoring chronic heart failure therapyReview of available data on the ability of hemodynamic measurements to predict outcomes in patients with heart failure reveals conflicting results. Some studies suggest that hemodynamic parameters at rest or during exercise are significant independent predictors of out-come.3Metra M Faggiano P D'Aloia A Nodari S Gualeni A Raccagni D Dei Cas L Use of cardiopulmonary exercise testing with hemodynamic monitoring in the prognostic assessment of ambulatory patients with chronic heart failure.J Am Coll Cardiol. 1999; 33: 943-950Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar, 4Butler J Chromsky DB Wilson JR Pulmonary hypertension and exercise intolerance in patients with heart failure.J Am Coll Cardiol. 1999; 34: 1802-1806Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar Newer markers such as transpulmonary passage of albumin or findings on echo Doppler that approximate changes in estimated filling pressure may be helpful as markers of risk.5Sherman HL Avelar E Grossman PM Sachdev V Oral H Nicklas JM Armstrong WF Transpulmonary passage of Albunex as a marker of intracardiac hemodynamics and outcome in chronic congestive heart failure.Am Heart J. 2000; 139: 782-787Abstract Full Text PDF PubMed Scopus (7) Google Scholar, 6Martins S Soares RM Branco L Salomao S Antunes AM Noninvasive monitoring of pulmonary capillary wedge pressure in heart failure.Eur J Heart Fail. 2001; 3: 41-46Crossref PubMed Scopus (5) Google Scholar However, analysis of results from the FIRST trial of patients with advanced heart failure suggested that exercise capacity as assessed by the 6-minute walk test, not resting hemodynamic measurements, was predictive of outcome.7Adams K Sueta CA Califf RM Gheorgiade M Harrell F Uretsky B Swedberg K McKenna W Soler-Soler J Tomasko L Gender differences in survival in patients with advanced heart failure.Circulation. 1999; 99: 1816-1821Crossref PubMed Google Scholar, 8Shah MR Hasselblad V Gheorghiade M Adams KF Swedberg K Califf RM O'Connor CM Prognostic usefulness of the six-minute walk in patients with advanced congestive heart failure secondary to ischemic or nonis-chemic cardiomyopathy.Am J Cardiol. 2001; 88: 987-993Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar Even if a single snapshot of hemodynamics is not very predictive, other data suggest that serial changes in ejection fraction and peak oxygen consumption during exercise testing may be of greater value.9Florea VG Henein MY Anker SD Francis DP Chambers JS Ponikowski P Coats AJ Prognostic value of changes over time in exercise capacity and echocardiographic measurements in patients with chronic heart failure.Eur Heart J. 2000; 21: 146-153Crossref PubMed Scopus (72) Google ScholarData on the relationship between drug-induced changes in hemodynamics and outcomes are of particular interest. Angiotensin-converting enzyme inhibitor therapy produces sustained hemodynamic improvement, but early on a dissociation was observed between acute hemodynamic benefit and subsequent clinical outcomes.10Sharma S Deitchman D Eni JS Gelperin K Ilgenfritz JP Blumenthal M The hemodynamic effects of long-term ACE inhibition with fosinopril in patients with heart failure: Fosinopril Hemodynamics Study Group.Am J Ther. 1999; 6: 181-189Crossref PubMed Scopus (8) Google Scholar, 11Massie BM Kramer BL Topic N Lack of relationship between the short-term hemodynamic effects of captopril and subsequent clinical responses.Circulation. 1984; 69: 1135-1141Crossref PubMed Scopus (90) Google Scholar In contrast, hemodynamic response correlated better with drugs that had direct hemodynamic effects.12Massie B Ports T Chatterjee K Parmley W Ostland J O'Young J Haughom F Long-term vasodilator therapy for heart failure: clinical response and its relationship to hemodynamic measurements.Circulation. 1981; 63: 269-278Crossref PubMed Scopus (147) Google Scholar Interestingly, acute drug-induced changes in degree of pulmonary hypertension did not predict out-come in a group of high-risk patients undergoing evaluation for cardiac transplantation.13Levine TB Levine AB Goldberg AD Tobes AC Narins B Goldstein S Lesch M Acute reversibility of pulmonary hypertension predicts neither long-term hemodynamic response nor outcome in patients awaiting heart transplantation.Am J Cardiol. 1997; 79: 105-106Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar Other uncontrolled studies suggest that short-term success with “tailored” therapy with various medications in patients with severe heart failure is associated with a better outcome than inability to achieve hemodynamic targets.14Stevenson LW Tailored therapy before transplantation for treatment of advanced heart failure: effective use of vasodilators and diuretics.J Heart Lung Transplant. 1991; 10: 468-476PubMed Google Scholar, 15Stevenson LW Tillisch JH Hamilton M Luu M Chelimsky-Fallick C Moriguchi J Kobashigawa J Walden J Importance of hemodynamic response to therapy in predicting survival with ejection fraction less than or equal to 20% secondary to ischemic or nonis-chemic dilated cardiomyopathy.Am J Cardiol. 1990; 66: 1348-1354Abstract Full Text PDF PubMed Scopus (295) Google Scholar, 16Drazner MH Solomon MA Thompson B Yancy CW Tailored therapy using dobutamine and nitroglycerin in advanced heart failure.Am J Cardiol. 1999; 84: 941-943Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar Continued uncertainty over this approach, mainly because of the potential for selection of lower-risk patients based on favorable treatment response, led to the ESCAPE study. This trial will attempt to validate the tailored therapy approach in a prospective randomized controlled trial.17Shah MR O'Connor CM Sopko G Hasselblad V Califf RM Stevenson LW Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE): design and rationale.Am Heart J. 2001; 141: 528-535Abstract Full Text Full Text PDF PubMed Scopus (90) Google ScholarData on the relationship between outcomes and serial hemodynamic changes during drug therapy for heart failure are minimal. Despite concerns about the safety and efficacy of long-term administration of inotropic agents, recent data from an uncontrolled study of repeated administration of milrinone over several weeks in patients with end-stage heart failure showed sustained improvement in hemodynamics over 4-month follow-up.18Hatzizacharias A Makris T Krespi P Triposkiadis F Voyatzi P Dalianis N Kyriakidis M Intermittent milrinone effect on long-term hemodynamic profile in patients with severe congestive heart failure.Am Heart J. 1999; 138: 241-246Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar These findings again point to the complexity of predicting clinical benefit from pharmacologic interventions based on assessment of surrogate end points like hemodynamics.Although direct hemodynamic monitoring to improve the care of patients with chronic heart failure is intrinsically attractive, many studies suggest that other less invasive strategies are useful. Early results suggest that measurement of brain natriuretic peptide, now available as a point-of-care assay, is useful in identification of left ventricular dysfunction and may also predict adverse events during hospitalization and after discharge.19Maisel AS Practical approaches to treating patients with acute decompensated heart failure.J Card Fail. 2001; 7: 13-17Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar, 20Kazanegra R Cheng V Garcia A Krishnaswamy P Gardetto N Clopton P Maisel A A rapid test for B-type natriuretic peptide correlates with falling wedge pressures in patients treated for decompensated heart failure: a pilot study.J Card Fail. 2001; 7: 21-29Abstract Full Text Full Text PDF PubMed Scopus (389) Google Scholar Studies to determine if serial measurements of this neurohormone are useful should help in guiding the long-term management of patients with heart failure. Even less technical interventions involving disease management teams, the addition of a pharmacist or home monitoring by various means, may produce substantial improvement in morbidity.21Gattis WA Hasselblad V Whellan DJ O'Connor CM Reduction in heart failure events by the addition of a clinical pharmacist to the heart failure management team: results of the Pharmacist in Heart Failure Assessment Recommendation and Monitoring (PHARM) Study.Arch Intern Med. 1999; 159: 1939-1945Crossref PubMed Scopus (404) Google Scholar, 22De Lusignan S Wells S Johnson P Meredith K Leatham E Compliance and effectiveness of 1 year's home telemonitoring: the report of a pilot study of patients with chronic heart failure.Eur J Heart Fail. 2001; 3: 723-730Crossref PubMed Scopus (156) Google Scholar, 23Jerant AF Azari R Nesbitt TS Reducing the cost of frequent hospital admissions for congestive heart failure: a randomized trial of a home telecare intervention.Med Care. 2001; 39: 1234-1245Crossref PubMed Scopus (252) Google Scholar, 24Heidenreich PA Ruggerio CM Massie BM Effect of a home monitoring system on hospitalization and resource use for patients with heart failure.Am Heart J. 1999; 138: 633-640Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar, 25Constantini O Huck K Carlson MD Boyd K Buchter CM Raiz P Cooper GS Impact of a guideline-based disease management team on outcomes of hospitalized patients with congestive heart failure.Arch Intern Med. 2001; 161: 177-182Crossref PubMed Scopus (66) Google Scholar These findings bring into question what intervention is the most appropriate control for randomized trials attempting to show the efficacy of any serial physiologic measurement of chronic heart failure, hemodynamic or other. The strategy in the control group may be particularly important for morbidity end points such as rehospitalization in which disease management programs and even simple changes in process seem to have significant benefits.Although the points above emphasize the difficulty of developing effective strategies to guide management in chronic heart failure, they do not detract from the critical importance of this effort. Both from a clinical and economic standpoint, heart failure remains a major public health problem. Establishing a reliable method to optimize outcomes by monitoring treatment response would represent a major clinical advance. Careful consideration of measurements to make, end points to assess, and therapy in control patients will be essential to validate new approaches. Review of available data on the ability of hemodynamic measurements to predict outcomes in patients with heart failure reveals conflicting results. Some studies suggest that hemodynamic parameters at rest or during exercise are significant independent predictors of out-come.3Metra M Faggiano P D'Aloia A Nodari S Gualeni A Raccagni D Dei Cas L Use of cardiopulmonary exercise testing with hemodynamic monitoring in the prognostic assessment of ambulatory patients with chronic heart failure.J Am Coll Cardiol. 1999; 33: 943-950Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar, 4Butler J Chromsky DB Wilson JR Pulmonary hypertension and exercise intolerance in patients with heart failure.J Am Coll Cardiol. 1999; 34: 1802-1806Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar Newer markers such as transpulmonary passage of albumin or findings on echo Doppler that approximate changes in estimated filling pressure may be helpful as markers of risk.5Sherman HL Avelar E Grossman PM Sachdev V Oral H Nicklas JM Armstrong WF Transpulmonary passage of Albunex as a marker of intracardiac hemodynamics and outcome in chronic congestive heart failure.Am Heart J. 2000; 139: 782-787Abstract Full Text PDF PubMed Scopus (7) Google Scholar, 6Martins S Soares RM Branco L Salomao S Antunes AM Noninvasive monitoring of pulmonary capillary wedge pressure in heart failure.Eur J Heart Fail. 2001; 3: 41-46Crossref PubMed Scopus (5) Google Scholar However, analysis of results from the FIRST trial of patients with advanced heart failure suggested that exercise capacity as assessed by the 6-minute walk test, not resting hemodynamic measurements, was predictive of outcome.7Adams K Sueta CA Califf RM Gheorgiade M Harrell F Uretsky B Swedberg K McKenna W Soler-Soler J Tomasko L Gender differences in survival in patients with advanced heart failure.Circulation. 1999; 99: 1816-1821Crossref PubMed Google Scholar, 8Shah MR Hasselblad V Gheorghiade M Adams KF Swedberg K Califf RM O'Connor CM Prognostic usefulness of the six-minute walk in patients with advanced congestive heart failure secondary to ischemic or nonis-chemic cardiomyopathy.Am J Cardiol. 2001; 88: 987-993Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar Even if a single snapshot of hemodynamics is not very predictive, other data suggest that serial changes in ejection fraction and peak oxygen consumption during exercise testing may be of greater value.9Florea VG Henein MY Anker SD Francis DP Chambers JS Ponikowski P Coats AJ Prognostic value of changes over time in exercise capacity and echocardiographic measurements in patients with chronic heart failure.Eur Heart J. 2000; 21: 146-153Crossref PubMed Scopus (72) Google Scholar Data on the relationship between drug-induced changes in hemodynamics and outcomes are of particular interest. Angiotensin-converting enzyme inhibitor therapy produces sustained hemodynamic improvement, but early on a dissociation was observed between acute hemodynamic benefit and subsequent clinical outcomes.10Sharma S Deitchman D Eni JS Gelperin K Ilgenfritz JP Blumenthal M The hemodynamic effects of long-term ACE inhibition with fosinopril in patients with heart failure: Fosinopril Hemodynamics Study Group.Am J Ther. 1999; 6: 181-189Crossref PubMed Scopus (8) Google Scholar, 11Massie BM Kramer BL Topic N Lack of relationship between the short-term hemodynamic effects of captopril and subsequent clinical responses.Circulation. 1984; 69: 1135-1141Crossref PubMed Scopus (90) Google Scholar In contrast, hemodynamic response correlated better with drugs that had direct hemodynamic effects.12Massie B Ports T Chatterjee K Parmley W Ostland J O'Young J Haughom F Long-term vasodilator therapy for heart failure: clinical response and its relationship to hemodynamic measurements.Circulation. 1981; 63: 269-278Crossref PubMed Scopus (147) Google Scholar Interestingly, acute drug-induced changes in degree of pulmonary hypertension did not predict out-come in a group of high-risk patients undergoing evaluation for cardiac transplantation.13Levine TB Levine AB Goldberg AD Tobes AC Narins B Goldstein S Lesch M Acute reversibility of pulmonary hypertension predicts neither long-term hemodynamic response nor outcome in patients awaiting heart transplantation.Am J Cardiol. 1997; 79: 105-106Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar Other uncontrolled studies suggest that short-term success with “tailored” therapy with various medications in patients with severe heart failure is associated with a better outcome than inability to achieve hemodynamic targets.14Stevenson LW Tailored therapy before transplantation for treatment of advanced heart failure: effective use of vasodilators and diuretics.J Heart Lung Transplant. 1991; 10: 468-476PubMed Google Scholar, 15Stevenson LW Tillisch JH Hamilton M Luu M Chelimsky-Fallick C Moriguchi J Kobashigawa J Walden J Importance of hemodynamic response to therapy in predicting survival with ejection fraction less than or equal to 20% secondary to ischemic or nonis-chemic dilated cardiomyopathy.Am J Cardiol. 1990; 66: 1348-1354Abstract Full Text PDF PubMed Scopus (295) Google Scholar, 16Drazner MH Solomon MA Thompson B Yancy CW Tailored therapy using dobutamine and nitroglycerin in advanced heart failure.Am J Cardiol. 1999; 84: 941-943Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar Continued uncertainty over this approach, mainly because of the potential for selection of lower-risk patients based on favorable treatment response, led to the ESCAPE study. This trial will attempt to validate the tailored therapy approach in a prospective randomized controlled trial.17Shah MR O'Connor CM Sopko G Hasselblad V Califf RM Stevenson LW Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE): design and rationale.Am Heart J. 2001; 141: 528-535Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar Data on the relationship between outcomes and serial hemodynamic changes during drug therapy for heart failure are minimal. Despite concerns about the safety and efficacy of long-term administration of inotropic agents, recent data from an uncontrolled study of repeated administration of milrinone over several weeks in patients with end-stage heart failure showed sustained improvement in hemodynamics over 4-month follow-up.18Hatzizacharias A Makris T Krespi P Triposkiadis F Voyatzi P Dalianis N Kyriakidis M Intermittent milrinone effect on long-term hemodynamic profile in patients with severe congestive heart failure.Am Heart J. 1999; 138: 241-246Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar These findings again point to the complexity of predicting clinical benefit from pharmacologic interventions based on assessment of surrogate end points like hemodynamics. Although direct hemodynamic monitoring to improve the care of patients with chronic heart failure is intrinsically attractive, many studies suggest that other less invasive strategies are useful. Early results suggest that measurement of brain natriuretic peptide, now available as a point-of-care assay, is useful in identification of left ventricular dysfunction and may also predict adverse events during hospitalization and after discharge.19Maisel AS Practical approaches to treating patients with acute decompensated heart failure.J Card Fail. 2001; 7: 13-17Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar, 20Kazanegra R Cheng V Garcia A Krishnaswamy P Gardetto N Clopton P Maisel A A rapid test for B-type natriuretic peptide correlates with falling wedge pressures in patients treated for decompensated heart failure: a pilot study.J Card Fail. 2001; 7: 21-29Abstract Full Text Full Text PDF PubMed Scopus (389) Google Scholar Studies to determine if serial measurements of this neurohormone are useful should help in guiding the long-term management of patients with heart failure. Even less technical interventions involving disease management teams, the addition of a pharmacist or home monitoring by various means, may produce substantial improvement in morbidity.21Gattis WA Hasselblad V Whellan DJ O'Connor CM Reduction in heart failure events by the addition of a clinical pharmacist to the heart failure management team: results of the Pharmacist in Heart Failure Assessment Recommendation and Monitoring (PHARM) Study.Arch Intern Med. 1999; 159: 1939-1945Crossref PubMed Scopus (404) Google Scholar, 22De Lusignan S Wells S Johnson P Meredith K Leatham E Compliance and effectiveness of 1 year's home telemonitoring: the report of a pilot study of patients with chronic heart failure.Eur J Heart Fail. 2001; 3: 723-730Crossref PubMed Scopus (156) Google Scholar, 23Jerant AF Azari R Nesbitt TS Reducing the cost of frequent hospital admissions for congestive heart failure: a randomized trial of a home telecare intervention.Med Care. 2001; 39: 1234-1245Crossref PubMed Scopus (252) Google Scholar, 24Heidenreich PA Ruggerio CM Massie BM Effect of a home monitoring system on hospitalization and resource use for patients with heart failure.Am Heart J. 1999; 138: 633-640Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar, 25Constantini O Huck K Carlson MD Boyd K Buchter CM Raiz P Cooper GS Impact of a guideline-based disease management team on outcomes of hospitalized patients with congestive heart failure.Arch Intern Med. 2001; 161: 177-182Crossref PubMed Scopus (66) Google Scholar These findings bring into question what intervention is the most appropriate control for randomized trials attempting to show the efficacy of any serial physiologic measurement of chronic heart failure, hemodynamic or other. The strategy in the control group may be particularly important for morbidity end points such as rehospitalization in which disease management programs and even simple changes in process seem to have significant benefits. Although the points above emphasize the difficulty of developing effective strategies to guide management in chronic heart failure, they do not detract from the critical importance of this effort. Both from a clinical and economic standpoint, heart failure remains a major public health problem. Establishing a reliable method to optimize outcomes by monitoring treatment response would represent a major clinical advance. Careful consideration of measurements to make, end points to assess, and therapy in control patients will be essential to validate new approaches.