Growing Mismatch Between Evidence Generation and Implementation in Heart Failure

Abstract

Heart failure is a leading cause of morbidity and mortality globally. The natural history of heart failure with reduced ejection fraction (HFrEF) has been altered with the development of multiple therapeutic agents targeting maladaptive biologic pathways, including angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers, beta-blockers, and mineralocorticoid receptor antagonists. Although mechanistic studies overlapped, the landmark trials and their publications that led to the acceptance of these therapies as standards of care generally occurred sequentially. Such evolution allowed for each therapy to be viewed as incremental to a patient population on the optimal background therapy. This traditional path of drug development has become more complex in the recent past. The Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial showed superiority of sacubitril/valsartan, an angiotensin receptor–neprilysin inhibitor, over enalapril.1McMurray JJ Packer M Desai AS et al.Angiotensin-neprilysin inhibition versus enalapril in heart failure.N Engl J Med. 2014; 371: 993-1004Crossref PubMed Scopus (3384) Google Scholar While the use of this therapy continues to slowly evolve, the Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure (DAPA-HF) trial (NCT03036124), the first large, outcomes trial to report the effects of sodium-glucose co-transporter-2 inhibitor in heart failure, showed that dapagliflozin reduced its primary composite endpoint (cardiovascular mortality, heart failure hospitalization, or urgent heart failure visit), and all-cause mortality (at nominal significance) in patients with HFrEF. Additionally, multiple ongoing trials are planning to report full results in the near future, evaluating myosin activators (omecamtiv mecarbil), soluble guanylate cyclase stimulators (vericiguat),2Armstrong PW Roessig L Patel MJ et al.A multicenter, randomized, double-blind, placebo-controlled trial of the efficacy and safety of the oral soluble guanylate cyclase stimulator: The VICTORIA Trial.JACC Heart Fail. 2018; 6: 96-104Crossref PubMed Scopus (86) Google Scholar and other SGLT2 inhibitors in HFrEF. This recent accelerated drug development and near-simultaneous evaluation of multiple novel agents have created a rich and exciting landscape poised to redefine modern treatment of HFrEF. Despite these advances in therapeutic options, clinical practice data continues to show that guideline-directed medical therapy (GDMT) for HFrEF remains at disappointingly low levels, and few patients, for multiple reasons, are actually on optimal therapy.3Greene SJ Butler J Albert NM et al.Medical therapy for heart failure with reduced ejection fraction: the CHAMP-HF Registry.J Am Coll Cardiol. 2018; 72: 351-366Crossref PubMed Scopus (344) Google Scholar,4Greene SJ Fonarow GC DeVore AD et al.Titration of medical therapy for heart failure with reduced ejection fraction.J Am Coll Cardiol. 2019; 73: 2365-2383Crossref PubMed Scopus (160) Google Scholar From an evidence generation perspective, this issue has another dimension of concern. If a therapy is evaluated when patients, at baseline, are not on 'optimal 'medical therapy, how do we assess its incremental value? At least for ACEI, beta-blockers, and mineralocorticoid receptor antagonists, patients were by design on as tolerated GDMT as background therapy. However, for patients enrolled in recent trials, because evidence generation is occurring in parallel and not in sequence, the majority of patients may not be on “optimal GDMT at baseline,” the definition of which itself is evolving. For instance, in the DAPA-HF trial, only ~1 in 10 patients were on baseline angiotensin receptor–neprilysin inhibitor therapy. This issue with low baseline therapy will compound in ongoing trials as well. Is it time for traditional stepped regimens to give way to more nuanced care with a menu of options, with investment in an implementation framework to meet the pace of evidence generation and help us choose wisely? Current efforts in evidence generation will not live up to their promise if they do not translate into clinical use. It is imperative that we develop an implementation framework dedicated to the understanding of strategies to best accelerate the adoption of disease-modifying therapies among eligible patients. This framework will require collaboration across academia, industry, payers, and health systems, and will need to be evaluated with similar rigor and high quality evidence that we hold to the study of new therapeutic modalities. Implementation avenues must be safe, effective, scalable, and generalizable. Implementation trials should be conceived at the time of planning the efficacy trials, allowing for staged implementation science to be completed and therapeutic uptake to be optimized. Though the methods and mechanisms of action of this implementation framework may be complex, its integration into healthcare systems must be both simple and nimble. Successful strategies will have to rely on design and funding of implementation trials and utilization of the emergence of health data science. These efforts must aim to simplify prescribing, relieve provider therapeutic inertia, allow less onerous monitoring, and improve patient compliance. The initial step in an implementation framework should include implementation trials that may borrow methodologically from traditional clinical trials. Specific early aims should include evaluation of strategies for early initiation and faster titration of any given therapy and determining optimal and tailored combinations of HFrEF therapies. Potential trials should include considerations surrounding the optimal setting for drug initiation (in hospital vs outpatient), the effect of direct patient-facing interventions, and the use of non-physician partners for protocol-based care provision. Dedicated multidisciplinary teams may be needed to optimize GDMT, both in inpatient and ambulatory settings.5O'Connor CM Guideline-directed medical therapy clinics: a call to action for the heart failure team.JACC Heart Fail. 2019; 7: 442-443PubMed Google Scholar Implementation trials must be complemented by utilization of emerging health data science. These analytic advances will allow for collation and analysis of large, multi-input datasets, and should be used to aid clinicians in drug selection, initiation, uptitration, and monitoring (Figure). For example, evaluation of a number of patient characteristics may be used to suggest patterns of disease in which particular therapeutics may be preferable or more efficacious. Using health data science to develop these pathways will be critical as the menu of heart failure pharmacotherapies expands, particularly if patients are unwilling or unable to take a multitude of drugs. In addition, clinical decision support systems leveraging broad sources of data beyond the traditional office visit, such as digital health data to monitor health status, symptoms surveys, and laboratory findings, may offer opportunities for the optimal timing of new drug initiation or dose uptitration. Such systems may also be used to monitor for drug off-target effects, elucidating earlier trends toward adverse effects and the need for follow-up, monitoring, or changes in pharmacotherapy. To translate the successes of our science to practice at the pace we need, we must invest fully and deeply in an implementation framework at all levels. We must commit to generating new data and phenotyping techniques that will allow for both scale and personalization. At the same time, we must realize the need for independent entities that can rigorously and expeditiously assess the value of emerging therapeutics. This critical assessment may allow for more data-driven, value-based decision-making about coverage and prioritization of care. In whole, these efforts will take immense cooperation between multiple stakeholder including clinicians, researchers, payers, and health systems, but such efforts will bear fruit that will be applicable across other chronic conditions.