Pub Date: Thursday, Aug 18, 2022
Author: James E. Udelson, MD
Affiliation: Division of Cardiology, the CardioVascular Center, Tufts Medical Center, Boston MA
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.
Jurgens CY, Lee CS, Aycock DM, Masterson Creber R, Denfeld QE, DeVon HA, Evers LR, Jung M, Pucciarelli G, Streur MM, Konstam MA; on behalf of the American Heart Association Council on Cardiovascular and Stroke Nursing; Council on Hypertension; and Stroke Council. State of the science: the relevance of symptoms in cardiovascular disease and research: A scientific statement from the American Heart Association [published online ahead of print August 18, 2022]. Circulation. doi: 10.1161/CIR.0000000000001089
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- Fanaroff AC, Kaltenbach LA, Peterson ED, Hess CN, Cohen DJ, Fonarow GC, Wang TY. Management of Persistent Angina After Myocardial Infarction Treated With Percutaneous Coronary Intervention: Insights From the TRANSLATE-ACS Study. J Am Heart Assoc. 2017 Oct 19;6(10):e007007. doi: 10.1161/JAHA.117.007007. PMID: 29051217; PMCID: PMC5721884.
- Trinkley KE, Kahn MG, Allen LA, Haugen H, Kroehl ME, Lin CT, Malone DC, Matlock DD. Patient Treatment Preferences for Heart Failure Medications: A Mixed Methods Study. Patient Prefer Adherence. 2020 Nov 10;14:2225-2230. doi: 10.2147/PPA.S276328. PMID: 33204073; PMCID: PMC7667168
- https://www.novartis.us/sites/www.novartis.us/files/entresto.pdf?cldi=PP1134 Accessed July 4, 2022
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- McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR; PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014 Sep 11;371(11):993-1004. doi: 10.1056/NEJMoa1409077. Epub 2014 Aug 30. PMID: 25176015.
- McMurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Anand IS, Bělohlávek J, Böhm M, Chiang CE, Chopra VK, de Boer RA, Desai AS, Diez M, Drozdz J, Dukát A, Ge J, Howlett JG, Katova T, Kitakaze M, Ljungman CEA, Merkely B, Nicolau JC, O'Meara E, Petrie MC, Vinh PN, Schou M, Tereshchenko S, Verma S, Held C, DeMets DL, Docherty KF, Jhund PS, Bengtsson O, Sjöstrand M, Langkilde AM; DAPA-HF Trial Committees and Investigators. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. 2019 Nov 21;381(21):1995-2008. doi: 10.1056/NEJMoa1911303. Epub 2019 Sep 19. PMID: 31535829.
- Packer M, Colucci WS, Sackner-Bernstein JD, Liang CS, Goldscher DA, Freeman I, Kukin ML, Kinhal V, Udelson JE, Klapholz M, Gottlieb SS, Pearle D, Cody RJ, Gregory JJ, Kantrowitz NE, LeJemtel TH, Young ST, Lukas MA, Shusterman NH. Double-blind, placebo-controlled study of the effects of carvedilol in patients with moderate to severe heart failure. The PRECISE Trial. Prospective Randomized Evaluation of Carvedilol on Symptoms and Exercise. Circulation. 1996 Dec 1;94(11):2793-9. doi: 10.1161/01.cir.94.11.2793. PMID: 8941104.
- Hicks KA, Mahaffey KW, Mehran R, Nissen SE, Wiviott SD, Dunn B, Solomon SD, Marler JR, Teerlink JR, Farb A, Morrow DA, Targum SL, Sila CA, Hai MTT, Jaff MR, Joffe HV, Cutlip DE, Desai AS, Lewis EF, Gibson CM, Landray MJ, Lincoff AM, White CJ, Brooks SS, Rosenfield K, Domanski MJ, Lansky AJ, McMurray JJV, Tcheng JE, Steinhubl SR, Burton P, Mauri L, O'Connor CM, Pfeffer MA, Hung HMJ, Stockbridge NL, Chaitman BR, Temple RJ; Standardized Data Collection for Cardiovascular Trials Initiative (SCTI). 2017 Cardiovascular and Stroke Endpoint Definitions for Clinical Trials. Circulation. 2018 Feb 27;137(9):961-972. doi: 10.1161/CIRCULATIONAHA.117.033502. PMID: 29483172.
- Jurgens CY, Lee CS, Aycock DM, Masterson Creber R, Denfeld QE, DeVon HA, Evers LR, Jung M, Pucciarelli G, Streur MM, Konstam MA; on behalf of the American Heart Association Council on Cardiovascular and Stroke Nursing; Council on Hypertension; and Stroke Council. State of the science: the relevance of symptoms in cardiovascular disease and research: a scientific statement from the American Heart Association [published online ahead of print August 18, 2022]. Circulation. doi: 10.1161/CIR.0000000000001089
- Olivotto I, Oreziak A, Barriales-Villa R, Abraham TP, Masri A, Garcia-Pavia P, Saberi S, Lakdawala NK, Wheeler MT, Owens A, Kubanek M, Wojakowski W, Jensen MK, Gimeno-Blanes J, Afshar K, Myers J, Hegde SM, Solomon SD, Sehnert AJ, Zhang D, Li W, Bhattacharya M, Edelberg JM, Waldman CB, Lester SJ, Wang A, Ho CY, Jacoby D; EXPLORER-HCM study investigators. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2020 Sep 12;396(10253):759-769. doi: 10.1016/S0140-6736(20)31792-X. Epub 2020 Aug 29. Erratum in: Lancet. 2020 Sep 12;396(10253):758. PMID: 32871100.
- Armstrong PW, Lam CSP, Anstrom KJ, Ezekowitz J, Hernandez AF, O'Connor CM, Pieske B, Ponikowski P, Shah SJ, Solomon SD, Voors AA, She L, Vlajnic V, Carvalho F, Bamber L, Blaustein RO, Roessig L, Butler J; VITALITY-HFpEF Study Group. Effect of Vericiguat vs Placebo on Quality of Life in Patients With Heart Failure and Preserved Ejection Fraction: The VITALITY-HFpEF Randomized Clinical Trial. JAMA. 2020 Oct 20;324(15):1512-1521. doi: 10.1001/jama.2020.15922. Erratum in: JAMA. 2021 Feb 2;325(5):494. PMID: 33079152; PMCID: PMC7576403
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-- The opinions expressed in this commentary are not necessarily those of the editors or of the American Heart Association --