Ambulatory Hemodynamic Monitoring in the Management of Pulmonary Arterial Hypertension

LIMITATIONS OF RHC

Though RHC can be performed very safely with low complication rates,7 accurate assessment of invasive hemodynamics requires rigorous attention to detail. This starts with equipment setup to ensure accurate leveling of pressure transducers and the zero line, as misleveling in and of itself can lead to inaccurate pressure measurements.8

In many PH patients, especially those with some degree of associated lung disease, hemodynamic pressure recordings are subject to significant respiratory variation in PA pressures and wedge pressure. This requires careful scrutiny of each measured parameter by an experienced clinician, with measurements ideally taken consistently at end expiration.8 Errors in measurement of the wedge pressure using mean rather than end-expiratory wedge pressure, for example, can lead to the misclassification of pulmonary venous hypertension as PAH, and similarly, underwedging of the PA catheter can lead to an erroneous diagnosis of left heart-related PH in patients with PAH.

In many centers, RHC for the evaluation of PAH is also typically performed at rest and in the recumbent, supine position. This is a somewhat artificial situation and is clearly not the hemodynamic state that most patients spend the majority of their lives in. Hemodynamics obtained in this condition may underestimate the severity of PAH and functional limitations with activity.

Indeed, the biggest limitation inherent to RHC is that it only provides a snapshot of a patient's hemodynamics at a single time point, akin to a solitary office blood pressure in patients with systemic hypertension. In the latter patient population, home or ambulatory blood pressure monitoring has shown the potential for dramatic variability in blood pressure over the course of a 24-hour period and from day to day, which is not necessarily reflected by a solitary office blood pressure recording.910 In patients with PAH, it is certainly not practical to obtain daily or even weekly RHC in ambulatory outpatients, and without ongoing knowledge of the patient's hemodynamics in the home and outpatient setting, the clinician is forced to make his/her best judgment in terms of PAH therapy based on the hemodynamic snapshot afforded by RHC.

POTENTIAL ADVANTAGES AND CLINICAL UTILIZATION OF AMBULATORY HEMODYNAMIC MONITORS

EXPERIENCE WITH CURRENT AMBULATORY HEMODYNAMIC MONITORING SYSTEMS

At present, 2 IHM systems have been studied in patients with congestive heart failure with left heart-related PH (WHO Group 2), and one system has been evaluated in a limited number of PAH patients. A comparison of these systems is illustrated in Table 1.

Table 1. Comparison of Medtronic Chronicle and CardioMEMs Hemodynamic Monitors

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The Medtronic Chronicle system (Medtronic, Minneapolis, MN) is an implanted device similar in appearance to a pulse generator of a pacemaker with a transvenous lead and associated pressure sensor, which is positioned in the RV (Figure 1).21 This system can provide an RV systolic pressure, an estimated PA diastolic pressure, and a calculated mean PA pressure. In patients with left-sided HF, IHM data have been shown to provide accurate RV and PA pressure measurements vs simultaneous RHC hemodynamics,2122 as well as in a limited number of patients with PAH.23

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In the COMPASS-HF study of 274 New York Heart Association (NYHA) functional class III or IV HF patients, the IHM was shown to be safe with no pressure sensor failures and very rare system-related complications. Patients treated based on IHM data had a nonsignificant trend to reduction in HF-related hospitalizations, which failed to meet the efficacy endpoint.24 A subsequent study demonstrated that patients who maintained lower intracardiac pressures on long-term monitoring had lower risk of future hospitalization.25 Despite these data, the Medtronic Chronicle system has not received FDA approval in the United States for hemodynamic monitoring in HF patients. This is somewhat unfortunate, because clinical data using IHM in patients with PAH remains limited to small clinical studies and case series mainly with the Medtronic Chronicle system. The clinical data that do exist have revealed intriguing findings concerning the severity of PAH and the effects of medical therapy.

Use of the Medtronic Chronicle in 5 patients with PAH treated with inhaled iloprost revealed that the reduction in PA pressures with iloprost was much shorter-lived than previously thought, and the vasodilator effect was achieved for only 13% of the entire monitoring span.26 In addition, though iloprost consistently reduced PA pressure at rest, it did not change PA pressures at peak exercise and workload.27 In 2 PAH patients transitioned from iloprost to bosentan, IHM data allowed clinicians to see the acute efficacy of bosentan therapy, which was sustained and indeed more pronounced over a week of therapy, allowing for successful discontinuation of iloprost therapy.14 In a multicenter study of 24 patients with PAH who had the Medtronic Chronicle implanted prior to change in PAH therapy, IHM data identified 13 of 15 patients who improved 6-minute walk distance greater than 30 meters, and change in mean PA pressure on IHM monitoring correlated with change in 6-minute walk.13

The second IHM device that has been used extensively in HF patients is the CardioMEMS sensor (St. Jude's Medical, St. Paul, MN). This system uses a wireless pressure sensor (Figure 2), which is a passive implant placed in a distal branch of the pulmonary artery during an RHC procedure via a delivery catheter. The external measurement system is designed to acquire pressure information from the sensor implanted within the pulmonary artery. It is composed of a main unit, a detachable antenna, and the connectivity to export the pressure data to an external database (Figure 2). The CardioMEMS device allows measurement of PA systolic, diastolic, and mean pressures, and has an algorithm for cardiac output assessment.

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The CardioMEMS device was studied in 550 NYHA functional class III HF patients in the CHAMPION trial, and use of the hemodynamic data from the device showed a significant reduction in HF hospitalizations.16 A large proportion of these patients (59%) had WHO Group II PH, and the HF hospitalizations were similarly reduced in these patients. PH patients also had a significant reduction in the composite endpoint of death and HF hospitalization with ongoing knowledge of hemodynamics (HR 0.74, 95% CI 0.55 to 0.99, P=0.04).28 Moreover, a recent substudy of the CHAMPION trial suggested that WHO Group II PH was underdiagnosed by a baseline RHC when compared to the mean PA pressure on IHM monitoring over the first week of the study, and that patients with occult PH had higher hospitalization rates than those without any PH.18 Based on results of the CHAMPION trial, the CardioMEMS device has received FDA approval for the management of NYHA functional class III HF with HF hospitalization in the past year.

Though there is relatively little experience with use of the CardioMEMS device in the PAH population, the clinical rationale for using this device is similar to that with the Medtronic Chronicle with the potential advantage of a cardiac output assessment, though the cardiac output algorithm is yet to be fully validated. In patients with PAH and presumable normal wedge pressure, knowledge of mean PA pressure and cardiac output could thus give the clinician insight into PVR on an ongoing basis. Certainly larger clinical studies using IHM data in PAH patients are warranted before their use is adopted in routine clinical practice, and IHM data might be used as a surrogate endpoint in future PAH clinical trials. In light of this, the National Heart, Lung and Blood Institute has recently funded a “proof of concept” study utilizing the CardioMEMS device in conjunction with cardiac MRI in 20 PAH patients to explore the feasibility and safety of using these combined modalities as a means to improve outcome prediction and monitoring of treatment efficacy in this disease state.29

SAFETY OF DEVICE IMPLANTATION

Limited safety data exist for the use of IHM in patients with PAH. In the small case series and case reports of the use of IHM in patients with PAH, no safety concerns were reported with IHM implantation. In the CHAMPION trial of the CardioMEMS IHM in 550 patients with congestive heart failure, 48 (9.2%) patients had PH with a significant pulmonary vascular component, a clinical profile similar to that encountered in PAH.

In this patient subset, there was only a single device/system-related complication: an atrial tachyarrhythmia associated with the implantation RHC procedure.16 The device/system-related adverse event rate in this subgroup with PH with a significant pulmonary vascular component was not statistically different than the established rate of adverse events for RHC in PH (n=76 of 7218, 1.1%, P=0.401),7 and is also not statistically different than what was observed in the remaining CHAMPION cohort with NYHA Class III Heart Failure (n=7 of 508, 1.4%, P=0.517). This acceptable safety record in CHAMPION, in patients with comparable pulmonary vascular hemodynamic characteristics as PAH patients, provides a reasonable basis to expect an acceptable safety profile in PAH patients. In the COMPASS-HF study, which used the Medtronic Chronicle IHM in patients with NYHA Class III or IV HF, some of whom had PH, there were no pressure sensor failures, and system-related complications occurred in only 8% of patients, of which all but 4 were resolved.24

IMPLICATIONS AND FUTURE DIRECTIONS

Ambulatory hemodynamic monitoring holds great promise for the management of patients with PAH. IHM data might provide further insight into a given patient's physiology and response to pharmacological therapy, while potentially allowing for remote monitoring and decreasing the requirement for office visits and invasive hemodynamic assessment. Despite these potential advantages, there has been very limited efficacy and safety data in PAH patients with IHM monitoring strategies to date. With FDA approval of the first IHM for use in HF patients and growing experience at major centers with this technology, this is an ideal opportunity to evaluate this technology in a larger clinical trial in PAH patients.