Published online before print September 2, 2008, doi: 10.1161/CIRCULATIONAHA.108.773275
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(Circulation. 2008;118:1241-1249.)
© 2008 American Heart Association, Inc.
Heart Failure |
Effects of Continuous Aortic Flow Augmentation in Patients With Exacerbation of Heart Failure Inadequately Responsive to Medical Therapy
Results of the Multicenter Trial of the Orqis Medical Cancion System for the Enhanced Treatment of Heart Failure Unresponsive to Medical Therapy (MOMENTUM)
From the University of California, San Diego, San Diego (B.G.); Henry Ford Heart and Vascular Institute, Detroit, Mich (B.C.); Texas Heart Institute, Houston (R.M.D.); University of Alabama, Birmingham (R.B.); Medical University of South Carolina, Charleston (M.R.Z.); Advocate Christ Medical Center, Oak Lawn, Ill (M.S.); University of Medicine and Dentistry of New Jersey, Newark (M.K.); California Pacific Medical Center, San Francisco (E.H.); University of Maryland Medical Center, Baltimore (M.R.M.); Jefferson University, Philadelphia, Pa (P.M.); Ohio State University, Columbus (W.T.A.); University of Minnesota, Minneapolis (J.D.N.); Integra Group, Brooklyn Park, Minn (B.S.B.); Orqis Medical, Lake Forest, Calif (I.C.P.); and Tufts Medical Center, Boston, Mass (M.A.K.).
Correspondence to Marvin A. Konstam, MD, Tufts Medical Center, 750 Washington St, Box 108, Boston, MA 02111. E-mail mkonstam{at}tuftsmedicalcenter.org
Received February 13, 2008; accepted July 1, 2008.
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Abstract |
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Background— Prior investigations suggest that superimposing continuous flow on aortic flow (continuous aortic flow augmentation) produces vasodilation, cardiac unloading, and improved cardiac performance.
Methods and Results— We compared percutaneous continuous aortic flow augmentation (flow 
1.5 L/min for up to 96 hours) plus medical therapy versus medical therapy alone by randomizing 168 patients (device, n=109; control, n=59) hospitalized with heart failure, reduced left ventricular ejection fraction and cardiac index, elevated pulmonary capillary wedge pressure, and renal impairment or substantial diuretic requirement despite intravenous inotropes/vasodilators. The primary composite efficacy end point included pulmonary capillary wedge pressure (72 to 96 hours) and days alive out of hospital off mechanical support over 35 days. The population’s illness severity posed unique challenges. Enrollment ended early because of an inability to demonstrate significant benefit on the primary composite end point (device, 17.4%; control, 13.6%; P=0.45) in the face of excess device group bleeding. Pulmonary capillary wedge pressure decreased from 28.8±6.3 mm Hg (mean±SD) to 24.9±7.2 mm Hg (average, 72 to 96 hours) and 28.9±7.1 to 26.5±6.2 mm Hg in the device and control groups, respectively (between-group P=0.074). Cardiac index progressively increased in the device (2.05±0.53 to 2.44±0.52 L · min–1 · m–2) but not the control (between-group P<0.0001) group. Thirty-five–day Kansas City Cardiomyopathy Questionnaire Overall Summary scores increased by 38.4±22.7 and 31.2±26.0 points in the device and control groups (between-group P=0.10). Through 65 days, device-to-control hazard ratios were as follows: all-cause mortality, 1.05 (95% confidence interval, 0.60 to 1.82); death or heart failure hospitalization, 0.87 (95% confidence interval, 0.57 to 1.33); and heart failure hospitalization, 0.66 (95% confidence interval, 0.38 to 1.13). Major bleeds occurred in 16.5% in the device (7.3% treatment related) and 5.1% in the control (P=0.05) group.
Conclusions— Continuous aortic flow augmentation improved cardiac performance, improving cardiac index and pulmonary capillary wedge pressure, but statistical significance for the primary efficacy end point was not attained. Hemodynamic and clinical observations provide direction toward additional studies to further investigate the clinical effects of this treatment.
Key Words: heart-assist device • heart failure • hemodynamics • vasodilation
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Introduction |
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More than 1.1 million US hospitalizations for heart failure (HF) occur annually, with a 6-month rehospitalization rate of nearly 50%.1 Despite advances in chronic HF treatment, little recent progress has been made in the management of acute HF exacerbations.2 Although advances have occurred in the design and use of ventricular assist devices,3,4 a gap exists in the availability of readily implantable short-term devices that improve clinical status and outcomes in patients with an exacerbation of HF.
Editorial p 1223
Clinical Perspective p 1249
Continuous aortic flow augmentation (CAFA), producing modest continuous supplemental aortic flow, is achieved with a percutaneous system consisting of a miniature extracorporeal pump, an iliac arterial inflow catheter, and an outflow catheter terminating in the descending thoracic aorta. CAFA reduced left ventricular filling pressure and volumes while augmenting stroke volume and ejection fraction in a canine HF model.5 A possible mechanism for benefit is improved abnormal flow patterns along the aortic endothelial surface,6 yielding downstream vascular effects.7 We previously demonstrated that CAFA progressively reduced systemic vascular resistance and pulmonary capillary wedge pressure (PCWP) and increased cardiac index (CI) in 24 patients hospitalized with HF exacerbation.8
The Multicenter Trial of the Orqis Medical Cancion System for the Enhanced Treatment of Heart Failure Unresponsive to Medical Therapy (MOMENTUM) is a randomized trial examining the effects on hemodynamics and clinical outcomes of adding CAFA to standard medical therapy.
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Methods |
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Study Design
MOMENUTM methods were previously described in detail.9 We randomized patients hospitalized with an exacerbation of chronic HF and persistent hemodynamic and renal compromise either to the Cancion System (Orqis Medical Corp, Lake Forest, Calif) plus medical treatment or to medical treatment alone. The randomization ratio was initially 1:1 but was changed to 2:1 (device:control) after enrollment of 49 patients to increase experience with the device. This decision was made blinded to treatment effect.
Patient Population
Investigational review board approval was obtained at all 40 sites. All patients provided written, informed consent. MOMENTUM was designed to enroll 200 patients 18 to 90 years of age. Enrollment stopped at 168 as a result of Data and Safety Monitoring Board (DSMB) recommendation (see below). Inclusion criteria included left ventricular ejection fraction 35% and persistent clinical, hemodynamic, and renal derangement despite standard oral medication and treatment for at least 24 hours with at least 1 of the following drugs at minimum dosage (stable for at least 6 hours): dobutamine 2.5 µg · kg–1 · min–1, milrinone 0.3 µg · kg–1 · min–1, dopamine 5 µg · kg–1 · min–1, nesiritide 0.01 µg · kg–1 · min–1, nitroprusside 0.25 µg · kg–1 · min–1, or nitroglycerine 0.25 µg · kg–1 · min–1. Enrollment required a PCWP of 
18 mm Hg continuously for 12 hours and 20 mm Hg at time of randomization; CI <2.4 L · min–1 · m–2; and either serum creatinine >1.2 mg/dL or intravenous furosemide dose 120 mg daily or equivalent. During treatment, drugs and doses could be adjusted according to the investigator’s clinical judgment.
Exclusion criteria included recent Q-wave myocardial infarction or revascularization; severe lung disease; primary liver disease; serum creatinine >4.0 mg/dL; dialysis; resynchronization device implanted within 14 days; systolic blood pressure <80 mm Hg; need for cardiac mechanical support; platelet count <50 000/µL; international normalized ratio >1.5 in the absence of anticoagulation; systemic infection; cerebral vascular accident or transient ischemic attack within 3 months; active status on the cardiac transplantation list unless transplant was considered unlikely within 65 days; peripheral vascular disease with absent pedal pulse or evidence of limb ischemia; and significant uncorrected primary valvular disease.
Description of Device
CAFA is achieved with a pump, tubing, and two 12F arterial catheters that continuously recirculate blood from the iliac artery to the descending thoracic aorta (Figure 1). Insertion and removal are performed in the catheterization laboratory. Insertion details are described elsewhere.8,9 Blood is circulated by a bearingless, magnetically levitated centrifugal pump designed to minimize hemolysis and thrombosis that is activated by a magnetoelectric motor connected to a controller. Pump speeds of 3200 to 4600 RPM achieve 1.1- to 1.5-L/min flow rates (generally set between 1.4 and 1.5 L/min).
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In vitro and in vivo studies have shown little or no hemolysis with up to 5 days of system use. The protocol initially called for repeated unfractionated heparin boluses to achieve an initial activated clotting time of at least 300 to 350 seconds (depending on the measurement device) before insertion. Because activated partial thromboplastin times were frequently supratherapeutic during day 1, after 
50% enrollment, activated clotting time targets were replaced by a uniform heparin dose of 70 U/kg (7000 U maximum). Heparin was infused continuously for the duration of treatment, maintaining an activated partial thromboplastin time of 65 to 85 seconds.
Measurements
Hemodynamic measurements were obtained in an intensive care unit with the same equipment for a given patient. Measurements were performed at baseline (after randomization); at 1, 2, 4, and 8 hours; and every 8 hours through 96 hours.
End Points
The primary efficacy end point was an overall success composite based on technical (device group only), hemodynamic, and clinical success defined as follows: technical success (device group only), insertion and attainment of flow 1 L/min for 24 hours; hemodynamic success, mean PCWP decrease from baseline of 5 mm Hg calculated as the average of values at 72 to 96 hours; and clinical success, from days 1 to 35 after randomization, any of the following: 10 consecutive days alive out of hospital, no alternative mechanical support, absence of death, and absence of readmission for HF.
Secondary efficacy end points were change in serum creatinine at day 3, change in body weight at day 4, change in CI (72- to 96-hour average), change in amino-terminal pro-B-type natriuretic peptide (NT-proBNP) at day 3, and change in Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary score at 2 weeks and 35 days.
The primary safety end point was the number of patients with 1 of the following events during 65 days after randomization: death, limb ischemia, stroke, renal failure, pulmonary embolus, and bleeding. Two bleeding definitions were used: major bleed, defined by the Thrombolysis in Myocardial Infarction Study Group (www.timi.org) as signs of hemorrhage with decreased hemoglobin >5 g/dL with adjustments for transfusions, and any bleed, including all major bleeds plus hemorrhage with 2 U transfused during any 7-day period.
Statistical Design, Sample Size, and Data Analyses
The primary efficacy analysis used intent to treat, analyzing data strictly according to randomization group. Between-group comparisons used logistic regression analysis, testing at the 0.05 (2-sided) significance level. Randomizing 200 patients (125 to device, 75 to control) provided 82.8% power to detect a 20% absolute between-group difference, from 40% to 20%, with a 2-sided significance level of 0.05.
Duplicate PCWP measurements were averaged at each time point. If a PCWP value was unavailable but pulmonary artery diastolic pressure was available, then the missing value was estimated arithmetically from pulmonary artery diastolic pressure and previous PCWP values. When only pulmonary artery diastolic pressure was available throughout, pulmonary artery diastolic pressure alone was used to estimate PCWP. For time points when neither measurement was available, PCWP was imputed from the last value carried forward.
Changes from baseline (PCWP, CI, creatinine, NT-proBNP, and weight) were compared by use of ANCOVA. Time-to-event analyses were summarized with Kaplan–Meier analyses and Cox proportional-hazards regression.
KCCQ scores were analyzed with repeated-measures ANOVA with fixed effects for treatment group, time of assessment, and treatment-by-time interaction and a within-patient covariance structure. Imputation techniques explored the impact of missing values, including replacement of missing responses with worst-case values.
In the above analyses, covariates corresponding to protocol version (1:1 versus 2:1 allocation), baseline presence of cardiac resynchronization device, and sites pooled according to patients enrolled were included, along with treatment group. For continuous variables, baseline levels were included as covariates in analyses of change. Results are reported as mean±SD unless otherwise noted.
Committees
A Clinical Events Committee reviewed all serious adverse events related to the primary safety end point, including deaths, and adjudicated cause of death and rehospitalization, with documentation blinded to treatment status to the extent possible. Hospitalizations were categorized as cardiovascular and noncardiovascular and, if cardiovascular, a result of HF, device complication, or other cause. An independent DSMB was charged with reviewing summaries of safety and efficacy grouped by treatment after 30 patients completed the 65-day follow-up and every 6 months and providing recommendations on study management or termination based on safety concerns and a risk-to-benefit analysis. The DSMB carried out a formal interim analysis after 30 patients completed the 65-day follow-up and after approximately one half of the patients completed the 65-day follow-up.
Core Laboratories
Hemodynamic tracings were analyzed by an independent expert at the Medical University of South Carolina blinded to treatment assignment and time point. Plasma samples for NT-proBNP were analyzed at the Cardiovascular Research Laboratory of the Mayo Clinic with the Shionogi assay.10
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
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Results |
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Between September 22, 2004, and August 9, 2007, 168 patients were randomized, 109 to device and 59 to control. Enrollment was terminated prematurely following DSMB recommendation based on a review of data from the initial 130 patients as a result of futility in achieving statistically significant benefit for the primary efficacy end point and identification of excess bleeding events in the device group.
Prerandomization characteristics are listed in Table 1. The population was extremely sick, with markedly abnormal values for PCWP, CI, renal function parameters, and NT-proBNP despite medical therapy, including intravenous vasodilators and/or inotropic agents. Table 2 provides population percentages and dosing information for the most frequently prescribed drugs at baseline and postrandomization days 3 and 30.
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Among 109 patients randomized to device, 103 underwent Cancion system insertion. One patient withdrew consent before implant, and in the remaining 5 patients, 1 or both catheters could not be inserted because of arterial disease. Of the 103 patients, 96 (93.2%) achieved procedural success, defined as catheter insertion and flow 1 L/min for 24 hours. Of the remaining 7 patients, 6 experienced device malfunction caused predominantly by catheter kinking, and 1 had early removal because of melena. Among the 103 patients, 90 (87.4%) remained on pump for at least 48 hours, 67 (65.0%) for 72 hours, and 35 (34.0%) for 96 hours. Among patients with procedural success, median treatment duration was 94.5 hours (mean±SD, 82.7±19.4) with an average pump flow of 1.43±0.1 L/min. Regardless of treatment duration, all 168 patients were evaluated for the primary efficacy end point. Table 3 displays hemodynamic findings. No significant between-group difference was found in mean arterial pressure (P=0.57), but heart rate increased in the device group (P=0.031). Mean±SD PCWP decreased in the control group from 28.9±7.1 mm Hg to an average of 26.5±6.2 mm Hg at 72 to 96 hours and in the device group from 28.8±6.3 to 24.9±7.2 mm Hg (between-group P= 0.074). CI was unchanged in the control group but increased progressively and significantly in the device group from 2.05±0.53 L · min–1 · m–2 to an average value of 2.44±0.52 L · min–1 · m–2 at 72 to 96 hours (between-group P<0.0001) with a progressive decrease in systemic vascular resistance (between-group P=0.0002). Figure 2 shows the relationships between PCWP and CI over time. Device group patients displayed a progressive upward-leftward shift in the PCWP-CI relation, consistent with improved cardiac performance. Primary efficacy end point success (hemodynamic and clinical success for both groups plus technical success in the device group) was seen in 13.6% of the control group and 17.4% of the device group patients (P=0.45; Figure 3).
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Table 4 lists results for the secondary efficacy end points. No significant difference was found in serum creatinine, NT-proBNP, or body weight. KCCQ Overall Summary and Clinical Summary scores increased more in the device group than in the control group, but treatment differences were not significant (P=0.10 and 0.095, respectively). At week 2, 22 device and 16 control patients were missing a KCCQ assessment for reasons other than death; at day 35, these numbers were 16 and 17. The impact of missing data was explored with imputation techniques, including replacement of missing individual questions with worst-case values and replacement of completely missing questionnaires with worst-case values; results were directionally and quantitatively similar to the nonimputed results.
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Over 65 days, 37 (33.9%) and 19 (32.2%) deaths occurred in the device and control groups, respectively. Kaplan–Meier curves for all-cause mortality were similar in the 2 groups (P=0.87 by Cox regression; Figure 4). The vast majority of deaths were cardiovascular (95% in each group), attributed mostly to HF (device group, 84%; control group, 79%). Twenty-four device group patients (22.0%) and 9 control group patients (15.3%) received either alternative mechanical support or heart transplantation (P=0.32). For the combined end point of all-cause mortality or HF hospitalization, 58 patients (53.2%) in the device group and 34 (57.6%) in the control group experienced events (65-day hazard ratio, 0.87; 95% CI, 0.57 to 1.33; P=0.51). Thirty of 109 patients (27.5%) in the device group and 23 of 59 patients (39.0%) in the control group were rehospitalized for HF (hazard ratio, 0.66; 95% CI, 0.38 to 1.13; P=0.13; Figure 5).
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Table 5 lists the percentages of patients with serious adverse events qualifying for the primary safety end point over 65 days. Bleeding represented the most frequent treatment-related serious adverse event. Of the 18 major bleeds in the device group, 7 were at the catheter insertion site(s). Ten patients had bleeding after cardiac surgery (ventricular assist device placement or transplant), and 1 patient had an intracranial hemorrhage on day 4. Of the 3 major bleeds in the control group, 2 occurred after cardiac surgery, and 1 was from a chest tube placed for empyema. Two cases of limb ischemia occurred. One patient showed diminished peripheral perfusion after the catheter could not be advanced. The patient underwent thromboembolectomy with good results. In the second patient, loss of pedal pulse prompted device removal, resulting in return of distal perfusion without further sequelae.
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Discussion |
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Despite advances in chronic HF treatment, acute decompensated HF remains a major source of morbidity, mortality, and expense, with little clear evidence of benefit and significant safety concerns for currently available therapies.2,11–18 CAFA represents a novel treatment for which both animal and preliminary human investigations have provided evidence of hemodynamic benefit. In the present study, we conducted a randomized comparison of CAFA combined with intensive medical therapy versus medical therapy alone in exceptionally sick patients hospitalized with decompensated HF inadequately responsive to conventional treatment. Patients randomized to CAFA demonstrated progressive improvement in CI and PCWP, consistent with improved left ventricular performance. However, enrollment ended early because of an inability to demonstrate significant benefit on the primary composite end point in the face of excess device group bleeding.
In animal studies, 4 hours of CAFA resulted in progressively reduced left ventricular volumes and filling pressure, with increased stroke volume and ejection fraction.5 In a prior uncontrolled series of patients with HF exacerbation, we observed a progressive reduction in PCWP and an increase in CI, denoting a favorable shift in the Starling curve, with CAFA.8 Hemodynamic benefits persisted 24 hours after device removal, suggesting that CAFA breaks a vicious cycle in which reduced aortic flow drives peripheral vasoconstriction, increasing filling pressure and further reducing CI. These findings suggesting the potential for sustained clinical benefit served as a foundation for the present investigation.
In the present trial, we explored both short-term hemodynamic and longer-term clinical effects of up to 4 days of CAFA. Entry required substantial hemodynamic derangement and either reduced renal function or high-dose diuretic requirement despite intravenous inotrope and/or vasodilator treatment. These criteria were driven by regulatory considerations based on reluctance to provide device intervention to patients who were not extremely sick. The resulting population was probably the sickest acute HF population ever studied in a randomized controlled trial, as evidenced by baseline hemodynamics, renal function, serum sodium, and NT-proBNP. Two-month mortality rates were greater than those of other contemporary acute HF trials19,20 but similar to that observed in an investigation of destination ventricular assist devices.4
The most striking hemodynamic finding was an increase in CI, averaging 0.4 L · min–1 · m–2, a 20% increase over baseline. CI increased 0.5 L · min–1 · m–2 in half of the treatment group. Unlike a ventricular assist device, the artery-to-artery circuit does not directly replace or augment CI, so the CI increase does not occur instantaneously. Rather, it occurs progressively, associated with reduced systemic vascular resistance. The augmented CI and reduced PCWP represent an upward-leftward Starling curve shift, denoting improved left ventricular systolic performance. The control group showed no increase in CI, and the "flat" hemodynamic shift with modestly reduced PCWP is likely attributable to diuresis without improved cardiac performance.
The effect of CAFA on systemic vascular resistance suggests downstream vascular signaling, possibly originating within the aortic endothelium. Disturbances observed under conditions of low flow along the periphery of an in vitro arterial tree model6 may be normalized by CAFA, and such changes may influence the production of vasoactive mediators such as nitric oxide.7 Further work is needed to define the mechanisms of CAFA effects.
The primary efficacy end point was designed to demonstrate CAFA clinical efficacy with an achievable sample size. The overall success rate was substantially lower than anticipated from our feasibility study, resulting in loss of statistical power. In addition, the benefit from CAFA compared with medical therapy alone, although substantial for CI, was less than anticipated for PCWP. The control group trend toward greater weight reduction suggests more aggressive diuresis, perhaps linked to clinician knowledge of PCWP. Early trial termination reduced the power for demonstrating statistical significance for secondary end points.
The hemodynamic effects and trends toward fewer recurrent HF hospitalizations and improved health-related quality of life of CAFA21 are hypothesis generating and will inform additional investigation into potential clinical CAFA benefits. Caution is needed in the interpretation of KCCQ results, given their subjective nature and missing data in this sick population, although imputational analyses demonstrated no substantive differences from the primary analysis. Future studies should consider investigating a less sick population in which clinical benefits may be more pronounced.
The incidence of bleeding was significantly higher in the device group than the control group. The incidence was comparable to that seen in a recent analysis of intraaortic balloon pump use after myocardial infarction (without thrombolytic therapy).22 Future research should strive to reduce bleeding through refined patient selection, device insertion and management, and anticoagulation. The incidence of clinically relevant vascular injury or limb ischemia was extremely small, although care is needed in selecting patients and deploying this treatment. We excluded patients with clinically overt severe peripheral vascular disease.
Demonstrating clinical trial efficacy is exceptionally difficult in decompensated HF owing to patient instability and postrandomization treatment differences. Symptom-related end points contain the challenges of subjectivity and high inherent variability. Demonstrating longer-term outcome benefit from short-term interventions requires large sample sizes that often are not feasible in device trials, particularly when inclusion criteria are sufficiently restrictive to facilitate the likelihood of a clinical effect.
Evidence is lacking for outcome benefit from any intervention in decompensated HF. Of the drugs presently approved in the United States, only nesiritide demonstrated efficacy for any clinical end point in a randomized controlled trial, and that end point is dyspnea at 3 hours.16 The safety of many drugs, including nesiritide, inotropes, and diuretics, has been questioned.11,13–15,17,18 A similar paucity of clinical trial data exists supporting the use of devices. Findings with early in-hospital ultrafiltration showed no benefit on symptoms or health-related quality of life, although they suggested a reduction in HF rehospitalization.23 Ventricular assist devices are far more invasive, generally deployed for "salvage" of patients at imminent risk of death either as a bridge to transplantation3 or as longer-term (destination) treatment.4 The present investigation attempted to fill the gap between commonly prescribed treatments and salvage therapy by exploring the hemodynamic and clinical effects of percutaneous CAFA treatment in patients hospitalized with worsening HF inadequately responsive to routine medical treatment.
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Conclusions |
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In a population of exceptionally sick patients hospitalized with exacerbation of chronic HF inadequately responsive to medical therapy, this trial confirmed a hemodynamic effect of short-term CAFA. It did not demonstrate longer-term clinical benefit. Future investigation should seek to reduce the incidence of bleeding and to identify characteristics of patients for whom hemodynamic improvement might more effectively translate into clinical benefit. Finally, the hemodynamic findings encourage investigation of the potential clinical value of a longer-term CAFA device.
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Acknowledgments |
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Source of Funding
This work was funded by Orqis Medical Corp, Lake Forest, Calif.
Disclosures
Drs Greenberg, Czerska, Delgado, Bourge, Zile, Silver, Klapholz, Haeusslein, Mather, and Abraham are investigators and consultants for Orqis Medical. Drs Neaton and Brown are consultants for Orqis Medical; Irene C. Parker is an employee with stock options in Orqis Medical; and Dr Konstam is a part-time employee, serving as medical director with stock options in Orqis Medical.
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Clinical trial registration information—URL: www.clinicaltrials.gov. Unique identifier: NCT00357591
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Circulation 2008 118: 1217-1218.
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