Table 2.

Challenges Specific to Common Surrogate Endpoints Used in Early Phase Heart Failure Trials

Invasive Hemodynamics

• Multiple examples of dissociation between hemodynamic improvement (e.g., improved cardiac index) and subsequent worse clinical outcomes (e.g., flosequinan, milrinone).

• Cardiac index and ventricular filling pressures can change acutely with changes in loading conditions and contractility and may not necessarily represent intrinsic cardiac recovery.

• Current guidelines discourage routine PAC placement. Common indication for PAC is cardiogenic shock but most HF trials require patients to be normotensive or hypertensive, thus making trial enrollment challenging.

Change in Natriuretic Peptide (NP) Level

• Multiple examples of dissociation between treatment-related NP change and clinical outcomes (e.g., levosimendan, aliskiren).

• Comorbid atrial fibrillation may influence NP levels and hinder the ability of study therapy to decrease NP levels in HFrEF. The ability of a study therapy to meet an NP-defined endpoint may be influenced by the prevalence of AF in the overall trial population.

• A significant minority of HFpEF patients have normal NP levels. Other HFpEF patients may have only minimal baseline NP elevation and it is unclear to what degree this can be modified with therapy.

• Biological and analytical variability must be recognized in interpretation of serial NP measurments.

• Heterogeneity in how NP endpoints defined:

○ Intention-to-treat principle versus per-protocol/ ‘completers’ approach

○ Continuous absolute change versus categorical endpoint defined by threshold level of relative reduction from baseline (i.e., >30%)

Change in Troponin Level

• Limited understanding of the mechanisms of troponin elevation in HF

• Biological and analytical variability must be recognized in interpretation of serial troponin measurements (although may be less of a challenge compared to NPs).

Cardiac Imaging

• Ejection fraction and ventricular volumes can change acutely with changes in loading conditions and contractility and may not necessarily represent intrinsic cardiac recovery.

• Relationship between changes in diastolic function with therapy and subsequent clinical outcomes is poorly established in HFpEF.

• 2D echocardiography may present challenges with inter-reader variability, reproducibility, and image acquisition.

• CMR and PET imaging are available only at select specialized centers and at relatively high cost.

• Use of CMR limits enrollment of patients with implantable cardiac devices

Functional Capacity (e.g, peak VO2, 6MWD)

• Multiple examples of dissociation between change in exercise capacity and clinical outcomes (e.g., flosequinan, ramipril, carvedilol).

• Trial protocols subject to accentuated placebo effect whereby exercise capacity improves with familiarization with exercise protocol.

• Potential for uneven intensification of background therapy between study arms during follow-up to maintain symptomatic stability.

• 6MWD may suffer from modest reproducibility and variability in clinician “coaching” and patient effort from one visit to the next and between study sites.

• CPET testing only available at select centers and burden of serial intensive exercise examinations on patients may be a challenge for patient recruitment.

Quality of Life, Dyspnea Relief, and Other Patient-reported Outcomes

• Multiple examples of dissociation between change in quality of life and clinical outcomes (e.g., flosequinan, spironolactone).

• Potential for uneven intensification of background therapy between study arms during follow-up to maintain symptomatic stability.

• Multiple grading instruments available and often no clear consensus on which is the “gold standard.” Examples exist where a therapy (e.g., serelaxin) may improve a patient-reported outcome (e.g., dyspnea relief) as measured by one grading instrument but not another.

• Majority of acute HF patients experience rapid (e.g., within hours) and robust dyspnea relief with standard therapy. Dyspnea may no longer be severe by the time of patient enrollment and it may be difficult for investigational therapies to show incremental improvement in dyspnea relief over standard therapy.

6MD, 6-minute walk distance; CMR, cardiac magnetic resonance; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; NP, natriuretic peptide; PAC, pulmonary arterial catheter; PET, positron emission tomography