American Heart Association Scientific Statement on State-of-the-Science: The Relevance of Symptoms in Cardiovascular Disease and Research

Throughout training and practice, clinicians are constantly reminded about the primacy of understanding – and hopefully impacting – the natural history of cardiovascular disease states. This imperative is reinforced by the medical literature. Major epidemiologic studies document years-long trajectories of incident disease and the progression of disease. All of our major imaging modalities construct as their foundational knowledge base studies of thousands of subjects assessing prognostic value, the relation of the imaging findings at the time of testing to subsequent natural history outcomes. Large population observational databases of patients with heart failure examine the relation of markers at initial study such as ejection fraction or biomarkers to the trajectory of disease progression and risk of death.

Therapeutic development and commercialization also highly value impact on natural history and disease progression. It is clear from US FDA Guidance documents that approval of a new drug or device requires efficacy in terms of impact on outcomes with concomitant safety, but can also be achieved through a favorable effect on some valid measure of symptoms, accompanied by sufficient assurance of no adverse effect on outcomes (1). Yet, those who participate in the development process have sat through many trial design meetings during an early phase of development of a new drug or device, and when projecting forward to what pivotal trial endpoints might be, often hear the comment (usually from the sponsor) that an “outcome trial” direction is far more valuable, since that would lead to higher reimbursement post-approval than would a development that ends with an effect on symptoms alone as the basis for approval.

Focusing on two of the major syndromes we all encounter in a cardiovascular disease practice can be illustrative of how and why most attention has been paid to affecting natural history and outcomes and less so on addressing the symptomatic state. Among patients presenting with acute coronary syndromes, once the dust has settled on the presenting event, often via revascularization, the imperative of guideline-based therapies is virtually all directed at secondary prevention, and ideally the patient is discharged on multiple therapies directed at this goal (2). One of the major achievements in cardiovascular disease therapeutics over the past few decades has been the improvements in outcomes post-myocardial infarction, based on the aggressive use of secondary prevention strategies and the rigorous clinical trials that established their use. In contemporary practice, symptoms of angina post-discharge after an acute coronary syndrome hospitalization are relatively uncommon (3), and little attention is paid to the symptomatic state during the initial hospitalization, though that could be assessed post-discharge, especially during cardiac rehab sessions.

Heart failure is distinct, in that it is a clinical syndrome with both a potentially very unfavorable natural history but also one in which the majority of patients are limited on a daily basis by symptoms that interfere with quality of life or functional capacity. Patient preference studies show that when given choices of treatment outcomes from a therapeutic intervention, patients value symptom improvement associated with better quality of life at least as strongly as an impact on outcomes (4). And yet, for patients with heart failure and reduced ejection fraction (HFrEF), the contemporary four “foundational therapies” have regulatory approvals that all involve impact on outcomes and not on the symptomatic state or on functional capacity (5-8). Recent trials using modern instruments do show modest group effects on quality-of-life scores for sacubitril/valsartan and for sodium glucose transporter-2 inhibitors (9,10). Older studies of evidence-based beta-blockers show a mixed picture, with carvedilol for example reported to improve symptoms as assessed by NYHA class and patient- or physician assessed global score, but having no improvement in quality-of-life scores or in functional capacity (the latter likely related to the heart rate blunting properties which affect exercise physiologic responses) (11).

One of the major impediments over the years in understanding therapeutic impact on the symptomatic state is the challenging nature of symptom assessment, in clinical trials or in epidemiologic studies. Natural history outcomes are well defined. It is straightforward to know whether a participant has died or has been hospitalized, and somewhat more challenging to classify those outcomes as cardiovascular or heart failure for instance, but paradigms have been established to homogenize such assessments within and, across trials (12). Capturing “symptoms” or a change therein however is far more challenging. Symptoms are highly individualized, and patients may experience different expressions of the impact of a pathophysiology on how they feel. Myocardial ischemia is well known to be experienced by patients in many ways beyond classic angina pectoris. The pathophysiology of heart failure may be experienced as shortness of breath, fatigue, or inability to maintain usual function. Symptoms are subjective and even descriptors of intensity such as mild, moderate or severe may mean different things to different patients.

There has however been substantial progress over the years in the development of tools to assess symptoms in trials and observation studies, and the tide is shifting for many reasons. The current American Heart Association Scientific Statement on The Relevance of Symptoms in Cardiovascular Disease and Research from Jurgens and colleagues is a very timely compendium of that progress (13). The Statement documents the heterogeneous nature of symptoms related to cardiovascular diseases and provides a comprehensive tabulation of symptom assessment tools across a broad range of cardiovascular diseases. The report will be a valuable resource to investigators and clinicians

In the heart failure world, there are recent examples of trials focused on the symptomatic state as a basis for approval. For patients with hypertrophic cardiomyopathy, the myosin inhibitor mavacamten was recently approved based on a pivotal clinical trial showing an improvement in symptoms as assessed by NYHA class in conjunction with an improvement in functional capacity as assessed by cardiopulmonary exercise testing (14). For patients with heart failure and preserved ejection fraction, a trial program developing a soluble guanylate cyclase stimulator was designed to show improvement in quality-of-life as assessed by the Physical Limitation Score of the Kansas City Cardiomyopathy Questionnaire as well as functional capacity by 6-minute walk distance (15). The results were neutral, so we will not know (yet) how the community and payors would receive such information for a drug that would be ultimately approved.

Thus, the American Heart Association Scientific Statement on The Relevance of Symptoms in Cardiovascular Disease and Research from Jurgens and colleagues is a clear and welcome reminder that while understanding and impacting natural history remain of high importance, the populations being studied are full of individual patients, each with a personalized day-to-day impact of their disease on their lives, that needs substantial attention.