By Toni Bransford, M.D., FACC Senior Medical Director, Medical & Scientific Affairs, Cardiovascular Disease, Worldwide Clinical Trials
Heart failure is a complex syndrome that had not seen new drugs receive approval for decades, which may be due in part to the cost and complexity of large cardiovascular outcome studies. However, in the last few years, the drug ivabradine was approved to reduce heart failure hospitalizations and sacubitril/valsartan was approved to reduce death and heart failure hospitalizations, and is currently recommended to replace angiotensin converting enzyme inhibitors as first line therapy in patients that tolerate it to reduce events. These approvals demonstrate that the health authorities are open to alternative, innovative clinical trial designs that don’t circumvent safety and are still able to show efficacy. Novel endpoints are one way to achieve this goal without increasing overall clinical research costs for pharma companies and cardiovascular contract research organizations (CROs).
Novel Endpoints in Clinical Trial Design
The two most important events in chronic heart failure will be death and heart failure (HF) hospitalization. Data from the Centers for Medicare & Medicaid Services state the U.S. national average readmission rate for heart failure patients is now 23 percent. So, the readmission rate for HF patients is indisputably high; in part, because heart failure is an extraordinarily complex disease and the underlying reasons for readmissions in HF patients encompass a host of factors. The HF patient’s clinical course is marked by repeated hospitalizations with a failure to return to pre-admission functional status, leading to disease progression and ultimately death. Patients with more hospitalizations have a higher mortality rate. So counting up all the events that mark the clinical course downward decline, in a recurrent events analysis, would be an alternative way to design the endpoint.
Assuming your primary composite event is death and HF hospitalization, the traditional heart failure clinical trial design would analyze these endpoints in a time-to-first event analysis. However, with this type of analysis a lot of information is ignored after the first event. For example, if the patient in a five-year trial has a HF hospitalization in the first three months, he is more likely to have additional events in that following year and even later. However, only that first hospitalization will be recognized in a time-to-first event analysis. A recurrent events analysis will capture up to 40 percent of additional events that would have been censored in a traditional trial design.
This has been aptly shown in the SHIFT, CHARM, and EMPHASIS post hoc analyses (1-3). The power in this analysis comes from the additional information borne out in the excess of events. By adding more information into the endpoint events used in the analysis, you have a greater treatment effect and can lower the sample size comparably. Some of the issues with recurrent events design is that you are simply counting events without any prognostic information. However, it is a fallacy to think that there is only one type of analysis possible with a recurrent events design. Indeed, there are numerous varied statistical ways to analyze repeat events that are beyond the scope of this discussion. Additionally, evaluating the time difference between events is important prognostic information that is regularly included in a recurrent events design.
Accounting for Event Interactions that Will Invariably Occur
Another issue is accounting for event interactions that will invariably occur. If the composite endpoint is death and HF hospitalization, then the competing risk of both must be accounted for; first, because any admission with worsening heart failure accentuates the risk of death and second, because dead patients can only die once and can no longer be admitted for additional hospitalizations. Additionally, a patient’s risk for death increases with each hospitalization. However patients can’t have the second hospitalization until they’ve had the first hospitalization; they can’t have the third hospitalization before having the second hospitalization; and so on.
Finally, repeat hospitalizations tend to cluster in a subgroup of patients experiencing many more than the average number of hospital admissions during a given period of time. This is generally felt to be problematic with recurrent events design, with a small fraction of patients contributing disproportionately to the overall burden of events. Yet, it is also true that if these individuals could be identified, they would be appropriate targets for more intensive monitoring and treatment.
Many Reasons Exist for Considering Alternative Trial Designs
As you can see, there are many reasons to consider using this type of alternative trial design in cardiovascular clinical research for HF: greater treatment effect; smaller sample size; better characterization of a patient subgroup that can be targeted for more intensive therapy; and capturing more information, which is important for understanding the overall effect in patients. And of course, lest we forget, these changes can lead to a decrease in costs for the trial and potentially for the entire clinical research program. At the same time, it is important to include the health authorities in the clinical trial design discussion to ensure that they understand and agree with all measures for evaluating safety and efficacy.
1. Borer JS1, Böhm M, Ford I, et al. Effect of ivabradine on recurrent hospitalization for worsening heart failure in patients with chronic systolic heart failure: the SHIFT Study. Eur Heart J. 2012;33:2813-20.
2. Rogers JK, McMurray JJ, Pocock SJ, et al. Eplerenone in patients with systolic heart failure and mild symptoms: analysis of repeat hospitalizations. Circulation. 2012;126:2317-23.
3. Rogers JK, Pocock SJ, McMurray JJ, et al. Analysing recurrent hospitalizations in heart failure: a review of statistical methodology, with application to CHARM-Preserved. Eur J Heart Fail. 2014;16:33-40.