According to Lam et al. 2023 the field of heart failure has shown a remarkable transformation (1). Lam and others also state that the field has recorded survival cases among individuals and a reduced ejection fraction. Moreover, new therapies have also recorded improved outcomes in the ejection fraction treatment process, with promising results in the use of great strides.
Lam and others’ ideas remain seconded by Sapna et al. (2023), who also report on the success of heart failure clinical trials. Hence, it requires applause based on the little efforts they have made to enhance survival among individuals. In the Sapna and others article, various treatment methods have enhanced the success of the heart failure clinical trials (5). Sapna and others report heart transplants, artificial intelligence, remote monitoring, ventricular-assisted devices, and implantable devices in their article.
The University of Southampton British clinical trials remain among recently reported successful. The trial was carried out in 2023, where the patient was diagnosed with non-ischemic cardiomyopathy (NICM). Ideally, this type of heart failure causes abnormal rhythm rates that can trigger heart attacks or even deaths. Phil O’Donoghue, aged 53, accepted the trial based on the fact that his heart condition halted his day-to-day activities and his lifestyle. Before the trial, Phil was introduced to medications that even worsened his condition University of (Southampton, 2023, p. 1). Therefore, with the necessary precautions to undergo the trial, Phil was introduced to it, which showed a tremendous improvement in his heart condition. Therefore, with this existing evidence, it is clear that the healthcare field has continuous research to eliminate the existing limitations in heart failure clinical trials.
Although there have been successful trials, some scholars still report on the failed trials. For example, in the article by Packer (2016), the author pleads for forgiveness due to failed trials due to insufficient resources (1). In the article, Packer argues that the phase II successful trials have yet to be recorded or confirmed as they cannot meet the number of cases that confirm approval. Therefore, to succeed, the trials need investors who are ready to sponsor the third phase trials without fail. In this case, the leading cause for failed trials is capital to sponsor the process. Also, inadequate knowledge of the primary causes, such as phenotype segmentation and socioeconomic determinants of heart failure among individuals, contributes to failed trials.
Current State of Heart Failure Therapies
According to the American Heart Association, there are several drugs used to treat heart failure. The drugs help in lessening the adverseness in heart failure symptoms such as fatigue, dyspnoea, or swelling in the heart. The main goal of lessening the symptoms is to help the patient attend to the day-to-day activities or increase their physical state. Some associated drugs include ACE inhibitors, diuretics, Aldosterone Antagonists, Hydralazine and isosorbide dinitrate, and SGLT-2 Inhibitors (Ghionzoli et al., 2022. pp 1120). Apart from the pharmacological measures, research also calls for a change in lifestyle for heart failure patients. In an article by Camafort et al. (2023., p. 21), though the idea lacks enough research, HF patients must adopt the DASH diet, which is highly preferred over the Mediterranean diet. The Dash diet, a combination of fruits, vegetables, whole grains, and fat-free and low-fat dairy products, marks a remarkable improvement in the physical state, a reduction in blood pressure, and lowers cholesterol accumulation in the cardiac system (Wickman et al. 2021, pp.4424). With these recorded positive outcomes, the DASH diet remains part of the comprehensive plan for managing heart failure.
Despite the existing efforts to bring a healthy lifestyle to patients with heart failure, some studies call for more research in the area. For example, in an article by Severino et al. (2023, p. 1), having proper therapeutic steps in management is still challenging. Although medications exist to lessen the symptomatic presence among individuals, some of these medications do not consider certain aspects, such as age or the pathophysiological state of an individual. Heart failure clinical trials are meant to reduce deaths or excessive hospitalizations, but the therapies do not consider the side effects that may result alongside the treatment journey. When starting a heart failure management and treatment plan, it is advised that the patient starts with the drugs in order to stagnate the appearance of other symptoms; however, with the continued use of these drugs, the patient might be exposed to other challenging factors, especially in the physical state. Based on these concepts, the limiting factors include age difference, enough resources, and lack of knowledge in the ventricular ejection fraction; hence, more research is required to close this gap.
Challenges in Clinical Trial Design
Methodological Challenges Faced in Designing Clinical Trials for Heart Failure
Sykora et al. (2022, p. 1) argue that clinical trials need systematic panning based on planning, execution, and sampling. This systematic approach remains necessary for the reliability and validation of results. At this point, selecting the right population remains the only mechanism for preventing flawed methodology. Study participants in the clinical trials are always divided into two groups. One group acts as the control for the study in that it contrasts with the main aim of the study. After the study, the outcomes are compared, and conclusions are made based on the results. For example, in a study by Aquino (2021, p. 1), the two sample groups include the prodromal Alzheimer’s and Parkinson’s disease populations. Within these two groups, the researchers will come up with outcomes that can favor both groups or the medical treatments that vary between the two groups based on the nature of the disease.
Regarding heart failure clinical trials, the two groups remain categorized into proteinopathies with an exemption from modifying therapies. According to Aquino, there have been various interventions to help slow down the rate of prodromal Alzheimer’s and Parkinson’s disease with no success. Research states that patients with heart failure remain at risk of developing prodromal Alzheimer’s. The reason behind this relationship is due to reduced cerebral blood flow and dysfunctional neurovascular unit. When blood is not pumped adequately into the cognitive system, it highly promotes the prevalence of mental issues that later trigger Alzheimer’s. Moreover, a breakdown in the nervous system also calls for mobility issues. Although there has been an advancement in biomarkers in identifying individuals with these disorders, there are several challenges during this stage, especially in identifying eligible populations.
Issues Related to Patient Recruitment, Endpoints, and Trial Duration
Patient recruitment, endpoint selection, and trial duration are critical to the design and implementation of heart failure clinical trials, all of which can impact the generalizability and quality of trial results. Patient recruitment is complicated by the variety of subtypes that exist within the heart failure patient population; therefore, it is essential to include a study population that is as diverse and representative as possible to ensure that trial results can be applied to the heart failure population more broadly (Hussain et al., 2022, pp. 6). It is recommended to strike a balance between inclusion and exclusion criteria to maximize the study population, as well as to minimize patient reluctance and increased competition with other triage
The choice of endpoints is crucial; whereas many studies focus on mortality and hospitalization rates as the primary endpoints, symptoms or quality of life improvements might also be noteworthy (Hussain et al., 2022). There needs to be substantial proof linking surrogate endpoints—including biomarkers—to clinical outcomes before they can be used. Composite endpoints are widely used; however, each component should be assessed for clinical relevance, which includes multiple outcomes. Trial duration remains also influenced by the long-term nature of heart failure; hence, it is essential to balance documenting meaningful clinical results with avoiding too extended trials. Anticipated event rates, including hospitalization or death, are also crucial since low event rates can necessitate a lengthier study. The challenge is to ensure that trials are nimble enough to adapt to the evolving standard of care while preserving study integrity.
Ensuring real-world relevance is critical to the external validity of trial results. The trial results themselves may be accurate, but if they are derived from trials with overly restrictive criteria or were too short a duration, millions of patients far more complex than those in the clean, controlled, randomized study will not receive the benefits. As pointed out in the article, long-term follow-up is essential to understanding the durability of treatment effects and late-emerging safety concerns. As is the case in this trial, this must be balanced against considerable challenges related to patient retention. Therefore, involving patient advocates in trial design will provide valuable perspectives to ensure the needs of patients are remembered from the very beginning and considered throughout.
References
American Heart Association, 2023. Medications used to treat heart failure. (online). Available at <https://www.heart.org/en/health-topics/heart-failure/treatment-options-for-heart-failure/medications-used-to-treat-heart-failure > [Accessed on 4th FEB, 2024).
Aquino, C.H.D., 2021. Methodological issues in randomized clinical trials for prodromal Alzheimer’s and Parkinson’s disease. Frontiers in Neurology, 12, p.694329. https://doi.org/10.3389/fneur.2021.694329
Camafort, M., Park, S.M. and Kang, S.M., 2023. Lifestyle Modification in Heart Failure Management: Are We Using Evidence-Based Recommendations in Real World Practice? International Journal of Heart Failure, 5(1), p.21. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9902645/
Ghionzoli, N., Gentile, F., Del Franco, A.M., Castiglione, V., Aimo, A., Giannoni, A., Burchielli, S., Cameli, M., Emdin, M. and Vergaro, G., 2022. Current and emerging drug targets in heart failure treatment. Heart failure reviews, 27(4), pp.1119-1136. https://doi.org/10.1007/s10741-021-10137-2
Hussain, A., Misra, A. and Bozkurt, B., 2022. Endpoints in heart failure drug development. Cardiac Failure Review, 8. doi: 10.15420/cfr.2021.13
Lam, C.S., Docherty, K.F., Ho, J.E., McMurray, J.J., Myhre, P.L. and Omland, T., 2023. Recent successes in heart failure treatment. Nature Medicine, 29(10), pp.2424-2437. https://doi.org/10.1038/s41591-023-02567-2
Packer, M., 2016. The unbelievable folly of clinical trials in heart failure: the inconvenient truth about how investigators and guidelines weigh the evidence. Circulation: Heart Failure, 9(4), p.e002837. https://doi.org/10.1161/CIRCHEARTFAILURE.116.002837
Sapna, F.N.U., Raveena, F.N.U., Chandio, M., Bai, K., Sayyar, M., Varrassi, G., Khatri, M., Kumar, S. and Mohamad, T., 2023. Advancements in heart failure management: a comprehensive narrative review of emerging therapies. Cureus, 15(10). https://assets.cureus.com/uploads/review_article/pdf/195799/20231103-29635-1enilox.pdf
Severino, P., D’Amato, A., Prosperi, S., Myftari, V., Canuti, E.S., Labbro Francia, A., Cestiè, C., Maestrini, V., Lavalle, C., Badagliacca, R. and Mancone, M., 2023. Heart Failure Pharmacological Management: Gaps and Current Perspectives. Journal of Clinical Medicine, 12(3), p.1020. https://doi.org/10.3390/jcm12031020
Sykora, P., Marks, R., Falsini, B., Capodicasa, N., Miertus, S., Lorusso, L., Dondossola, D., Tartaglia, G., Ergoren, M., Dundar, M. and Michelini, S., 2022. Methodology for clinical research. Journal of preventive medicine and hygiene, 63(2 Suppl 3). https://doi.org/10.15167/2421-4248/jpmh2022.63.2s3.2769
University of Southampton. (2023). First Patients Enter Clinical Trial to Improve Heart Failure Treatment | University of Southampton. [online] Available at: https://www.southampton.ac.uk/news/2023/06/first-patients-enter-clinical-trial-to-improve-heart-failure-treatment.page [Accessed 4 Feb. 2024].
Wickman, B.E., Enkhmaa, B., Ridberg, R., Romero, E., Cadeiras, M., Meyers, F. and Steinberg, F., 2021. Dietary management of heart failure: DASH diet and precision nutrition perspectives. Nutrients, 13(12), p.4424. https://doi.org/10.3390/nu13124424
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