Author + information
- Christopher M. O’Connor, MD, FACC, Editor-in-Chief, JACC: Heart Failure∗ (, )
- Mona Fiuzat, PharmD, FACC, Executive Editor, JACC: Heart Failure and
- JoAnn Lindenfeld, MD, FACC, Deputy Editor, JACC: Heart Failure
- ↵∗Address for correspondence:
Dr. Christopher M. O’Connor, Editor-in-Chief, JACC: Heart Failure, American College of Cardiology, Heart House, 2400 N Street, NW, Washington, DC 20037.
It should come as no surprise that the implementation of evidence-based medicines, including new therapies approved by the Food and Drug Administration (FDA) in 2015, have experienced a slow uptake. Over the past 3 decades, we have seen the development of life-saving therapies such as angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, and mineralocorticoid receptor antagonists, now all used in clinical practice. During this time, it has taken up to 10 years to see the baseline rates of these medications from clinical trials increase from 10% up to 90% in appropriate patients, and over 17 years to achieve widespread use in clinical practice.
Why is this so? In 2012, the World Health Organization highlighted the importance of implementation science and research in translating breakthrough medicines into policy and practice. The challenge is that what is evident to work does not always translate into evidence as to why and where it works.
Why is there a resistance to the implementation of life-saving therapies? There are several reasons beyond the love of standard therapy.
1. The nature of the evidence that supports the implementation of the new therapy is extremely important. For the PARADIGM-HF trial (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure trial) (1) and sacubitril/valsartan (Entresto), the evidence is overwhelmingly positive. The reduction in heart failure hospitalizations and mortality, as well as the improvement in quality of life and the early reduction of death, all point to what we could consider a “grand slam” in therapeutic development in heart failure. On the basis of the evidence alone, there should be little resistance for the implementation of this new therapy. We would expect enrollment of patients on this new therapy to be slow, but evident. However, of notable concern to the FDA was insufficient evidence for either the safety relative to angioedema in black patients, or the risk of cognitive dysfunction with the use of Entresto (2). These concerns could obviously cause some pause in making this change.
2. A change in category of drug creates more uncertainty. For more than 3 decades, the cornerstone of baseline therapy for heart failure with reduced ejection fraction has been ACE inhibitors or angiotensin receptor blockers—therapies we have increased to 90% in heart failure patients over the last decade. Medical care providers have become quite expert in the dosing, indications, drug–drug interactions, and adverse effects of these renin-angiotensin system blockers. Now we are implementing a new type of therapy, the neprilysin inhibitor plus the renin-angiotensin system blocker, valsartan, and health care providers have no experience with dosing, drug–drug interactions, or adverse effects. The recommendation for this change has not been fully implemented in the heart failure clinical practice guidelines that health care providers often look to for guidance—especially in the face of unfamiliar new therapies. As noted in the supplemental editorial by Dr. Packer (3), many patients are still below guideline-recommended dosing; so perhaps it is not our love of ACE inhibitors but rather limitations in our current practice.
3. Current medical environment, health care systems, and practices have de-emphasized the implementation of novel therapies and have emphasized efficiency, value, and cost-effectiveness. This places an even greater burden on increasing the use of this new and relatively expensive drug. Furthermore, high copays and lack of insurance coverage have left a number of patients unable to pay for the drug.
4. There has been little facilitation of successful change. What have the sponsors done in response to this historically slow uptake of evidence-based therapies? There has been no implementation of widespread registries evaluating special populations and populations not studied in the clinical trial, which would provide further evidence both with respect to comfort and training for practicing clinicians in making the switch from ACE inhibitor therapy to Entresto.
5. There is a cost to the patient of switching therapies. When a therapy is changed, patients often have to have additional clinic visits and laboratory tests. In addition to copays for lab tests and visits, there are costs for travel and time off from work. In addition, there is often an emotional cost to changing therapies. This is in addition to the high cost of the therapy itself. The current list price is approximately $4,560 annually, which makes this one of the most expensive outpatient heart failure drugs to date. In this issue of JACC: Heart Failure, we see a cost-effectiveness analysis that puts this above the threshold for cost-effective therapy (4). A glimmer of hope comes with the recent announcement from 3 major insurance companies that they are contracting with the sponsor on pay-for-performance, outcome-based coverage agreement with the sacubitril/valsartan combination. Impressively, the payment will depend on relative improvements in patient health, including decrease in heart failure–related hospitalizations. The company, recognizing the challenges of rapid enrollment of patients, is suggesting that the medication should work better than expected with standard therapy, implying that the patients will receive equal or greater benefit than what was seen in the clinical trials. Therefore, the company is comfortable with outcomes-based contracts, requiring that prescription medications are performed in the real world. This unique risk-based contracting between insurance companies and the sponsor, and subsequently, between health care systems and the sponsor, is a novel and innovative approach to implement important life-saving therapies, specifically for those that will improve patient-related outcomes but that have to remain expensive due to the cost of their development over the 17 previous years.
In summary, the slow uptake of new therapies is more complicated than a love affair with the standard therapy. The implementation of evidenced-based medicines is complex and multifactorial. Recent challenges to the status quo by the risk-based contracting, providing greater resources for ongoing registries that can characterize special populations receiving the therapy, evidence addressing the FDA concerns around safety issues, continuing medical education–based programs, and partnering with societies and health systems to provide broad-based education for practitioners, will hopefully result in uptake such that it can beat the 10-year yardstick that we have seen with previous therapies.
Disclaimer: The information and conclusions presented in this Editor’s Page do not represent new FDA policy nor do they imply an imminent change in existing policy.
- American College of Cardiology Foundation
- ↵U.S. Department of Health and Human Services Food and Drug Administration. Letter of Approval for ENTRESTO. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2015/207620Orig1s000ltr.pdf. Accessed March 18, 2016.
- Packer M.
- King J.B.,
- Shah R.U.,
- Bress A.P.,
- Nelson R.E.,
- Bellows B.K.