CLINICAL RESEARCH MODELS FOR CORONARY SYNDROMES

Acute coronary syndromes (ACS) is a broad term referring to a group of conditions ranging from unstable angina, to myocardial infarction (heart attack), to sudden cardiac death. The condition depends on the degree to which the coronary artery has been obstructed and the health effects the obstruction has caused. A diagnosis of ACS is made by evaluating the results of an electrocardiogram (ECG) and the presence or absence of certain enzymes in the body.

Clinical research efforts in ACS provide a useful model for examining large, multicenter effectiveness trials in an acute, life-threatening disease. Robert Califf, Vice Chancellor for Clinical Research and Director of the Duke Translational Medicine Institute, reflected on the notable successes of the ACS field in translating basic science into early clinical trials, and then into definitive trials that evaluate outcomes related to key clinical questions. Once effective treatments have been identified and disseminated, the final step is measuring their uptake in hospitals and making the results publicly available, which improves adherence to the treatments. A 2004 study examining hospital compliance with quality guidelines (those of the American College of Cardiology/American Heart Association) and in-hospital mortality rates revealed that a 10 percent increase in guideline adherence corresponded to an 11 percent reduction in mortality rates (Peterson et al., 2004). Califf also cited papers based on data from a national registry of myocardial infarction showing that U.S. hospitals show close to 100 percent uptake of evidence-based therapies for ST elevation myocardial infarction (STEMI) and non-ST elevation myocardial infarction (non-STEMI) at both hospital admission and discharge. The result has been an approximately 30 percent reduction in the risk of death if a patient presents at a hospital with chest pain. Califf stressed that, to establish evidence-based therapies that individuals and institutions can be held accountable for using, clinical trials should be focused on answering the critical questions in that disease area; conversely, trials that are poorly designed and seek to answer peripheral or irrelevant questions should be avoided.

Califf reflected on the evolution of clinical trials in ACS. Califf was part of a small group of people who formed the TAMI Group to address the area of STEMI trials. The group received a small amount of money ($100,000) from Genentech to conduct a randomized controlled trial (RCT) with 340 participants. The trial protocol, or study plan, included three cardiac catheterizations per subject, and the trial results were published in the New England Journal of Medicine. Califf highlighted this example of an early ACS trial because he believes the same trial could not be conducted today given the extremely high cost of conducting trials and the large number of patients now required for cardiovascular outcome trials.

The International Study of Infarct Survival (ISIS) group at Oxford had a similar early trial experience that Califf likewise claimed could not be replicated in today’s clinical trial environment. The minimum sample size required to answer the study question of interest to the ISIS group was 10,000 patients. Using unpaid clinical investigators and a one-page case report form the ISIS group randomized the 10,000 patients necessary to answer the relevant clinical question. The ISIS trial changed the study of ACS in that future trials sought larger sample sizes to appropriately answer the main outcome questions of interest in cardiovascular disease. However, the fact that the ISIS trial did not pay investigators makes its duplication in any country today impossible, according to Califf. Another critical change in the conduct of STEMI trials came when the U.S. Food and Drug Administration (FDA) moved toward requiring outcome trials to evaluate critical clinical endpoints related to the safety and effectiveness of a drug. Califf explained that the new FDA standard for STEMI trials changed this field of research and improved the clinical relevance of trials conducted by industry and academia.

Recognizing a practical, clinical inception time for the spectrum of ACS improved the ability of practitioners to identify a study population. The primary medical action in ACS occurs in the first 24 hours of a patient’s hospital stay. In the past, diagnosing a type of ACS often required a patient to be admitted, receive an ECG, and have a physician evaluate enzyme levels 24 hours later to determine whether the patient had experienced a heart attack, and then for the physician to refer to the ECG results to determine whether it was STEMI or non-STEMI. Elliott Antman, Senior Investigator in the TIMI Study Group, developed a system for classifying patients at the time of the ECG (Figure 4-1). Califf explained that creating an easily identifiable marker by which to classify patients in the emergency room made it less expensive and time-consuming for busy practitioners to become involved in locating patients for a clinical trial. This practitioner-oriented classification system is especially helpful in facilitating enrollment in cardiovascular disease trials, which typically seek to recruit a large number of patients per trial. Box 4-1 presents a case study illustrating the importance of developing a practical disease inception point.

FIGURE 4-1

Classification system for the spectrum of acute coronary syndromes that helps practitioners identify a study population more easily. NOTE: MI = myocardial infarction. SOURCE: Califf, 2009. (Adapted from 2007 American Heart Association/American College (more...)

BOX 4-1

Case Study: Acute Decompensated Heart Failure and Acute Myocardial Infarction. The importance of developing a practical inception point for a disease is highlighted by comparing two diseases—acute decompensated heart failure and acute myocardial (more...)

THE THROMBOLYSIS IN MYOCARDIAL INFARCTION STUDY GROUP

As an example of a disease-focused research network, Marc Sabatine, investigator in the TIMI Study Group, discussed the group’s research work and structure. Headquartered at Brigham and Women’s Hospital and Harvard Medical School, TIMI is an academic research organization (ARO) conducting clinical trials to improve health outcomes in patients with cardiovascular disease. Conducting studies from phase I to IV, TIMI has completed 45 clinical trials to date, and has 6 ongoing trials and 7 in the planning stages. Trial sizes range from 30 to 25,000 subjects. Sabatine noted that the academic leadership at the core of TIMI’s work participates in each stage of the clinical trial process, including:

• Reviewing the compound—reviewing the pharmacokinetic (PK), pharmacodynamic (PD), animal model, and phase I data for a compound being considered for further study.
• Refining the scientific question—asking whether a new compound addresses an unmet clinical need in cardiovascular medicine, as well as what utility the compound has and how it relates to current and evolving concomitant treatments.
• Initiating the study—helping to plan and initiate both investigator- and industry-initiated studies.
• Developing study design—helping to determine the study population, the timing of the intervention, the appropriate control arm and background therapy, the endpoints and timing of ascertainments, and the statistical analysis plan.
• Developing key trial documents—collaborating on the development of the trial protocol, case report form, Clinical Events Committee (CEC) charter, and Data Safety Monitoring Board (DSMB) charter.
• Study startup—considering the country and site for a trial, the applicability of trial results in the United States, the acceptability of the trial to other countries, and the cost of conducting the trial.
• Monitoring study progress—monitoring patient enrollment, any changes in the medical landscape, aggregate event rates (efficacy and safety), and the retention of patients.
• Leading study analysis—conducting data analysis on a database separate from that received by trial sponsors and moving rapidly to present the data at scientific meetings, as well as drafting primary manuscript of the trial results and engaging in subsequent data analyses.

When Eugene Braunwald founded the group in 1984, TIMI trials were funded by the National Heart, Lung, and Blood Institute (NHLBI). Today the trials are funded by industry, with some NIH grant support for ancillary studies. In response to a question from Califf, Sabatine described TIMI’s studies as being relatively complex, having case report forms that are more than one or two pages, and seeking to answer a variety of questions. Strong academic support for the trial activities listed above is important to the group as a whole and would be very difficult to maintain through government funding alone.

Sabatine stated that one of the strengths of the TIMI group is the relative leanness of the organization. The physician staff includes the study chairman, 12 staff cardiologists, three senior cardiology fellows, and a rotating staff of research residents from Brigham and Women’s Hospital. Operational staff includes a director, eight project directors and managers, and research assistants. Core biostatistics staffs, including a director and multiple programmers, round out the TIMI group. Sabatine described an intense working relationship between physician staff and operational staff as important to ensuring that the trials are conducted in the best possible way. For a typical TIMI trial, two physicians and multiple operational staff work closely on planning and execution. Physician and operational staff offices are located next to one another, which facilitates daily conversations to guide a trial from inception to completion.

THE OCCLUDED ARTERY TRIAL

Lauer discussed OAT as a case study that highlights a number of common obstacles encountered in conducting a large clinical trial with significant ramifications for clinical practice.

Acute MI (heart attack) is caused by the occlusion of coronary arteries that supply blood to the heart. A cardiologist treating such a case can perform a percutaneous intervention (PCI), or cardiac catheterization, in which a stent is inserted to open the affected arteries. In the 1990s, observational studies showed a marked improvement in mortality rates for those patients with open arteries. As a result, there was a widespread increase in the use of cardiac catheterization to open the arteries of heart attack patients, and, despite the lack of robust scientific evidence supporting PCI, it became conventional medical wisdom to use this procedure for patients with chronically occluded arteries after a heart attack. OAT, an NHLBI-supported experimental trial, eventually revealed that health outcomes were worse among those subjects randomized to receive stents, dispelling the belief that opening arteries through PCI is always desirable. OAT illustrates the importance of basing medical decision making on well-controlled clinical experiments as opposed to observational correlations. According to Lauer, the trial is also an example of how the federal government can provide real value in clinical research, particularly when focusing on existing clinical practices for which evidence is lacking.

Lauer also explained that a number of logistical and administrative obstacles were encountered in running OAT. Each obstacle highlights the extent to which the incentives and interests of stakeholders, as well as regulatory burdens, can hinder a trial. As indicated in Figure 4-2, OAT included 2,166 patients and took 10 years to complete. Along the way, investigators encountered delays in grant review. Investigators also faced an unexpected requirement to conduct a pilot study, for which they received no funding, to improve their chances of ultimately receiving NIH funding. After final grant approval, of the 926 sites approached to participate in the study, only one-third agreed to do so. The investigators believe this unwillingness to participate was due partly to a pro-PCI bias on the part of physicians. Under this theory, because some physicians believed PCI was clearly the appropriate course of treatment, they saw no value in participating in a clinical trial to test this assumption. Some physicians claimed it would be unethical to assign patients to a control group that would receive the best medicine for the condition but not PCI. Califf suggested that the lack of physician interest in participating in this trial was also associated with the fact that PCI is a profitable procedure for physicians, and participation in the trial would randomize only a portion of their patients to receive the procedure, thus eliminating the opportunity to administer it to every patient.

FIGURE 4-2

Timeline for the NIH-sponsored Occluded Artery Trial (OAT). NOTE: NHLBI = National Heart, Lung, and Blood Institute; OAT = Occluded Artery Trial; OAT-NUC = Occluded Artery Trial Nuclear Study; TOSCA-2 = Total Occlusion Study of Canada-2. SOURCE: Lauer, (more...)

Recruiting patients to participate in the trial also created delays. Of those sites that did participate, only two-thirds enrolled at least one patient. One-third of the sites filled out all required paperwork and received Institutional Review Board (IRB) approval, but never enrolled a patient. The overall enrollment rate was 0.25 patients per site per month. Ultimately, only 488 of the 2,166 patients were enrolled from 85 U.S. sites; the vast majority of subjects had to be enrolled abroad.

According to Lauer, the OAT experience highlights a number of important points:

• Relying on the gold standard—RCTs remain the gold standard for proving the effectiveness of a drug or therapy. Observational data and unproven associations are susceptible to confounding and can be misinterpreted.
• Federally sponsored research—The federal government plays an important role in funding and conducting large clinical trials to test the effectiveness of clinical practices that are in widespread use but do not have an evidence base.
• Biases—Physicians and patients often have strong preferences for and biases toward certain procedures or levels of care they believe to be appropriate, regardless of the evidence supporting them.
• Misaligned financial incentives—Financial incentives for physicians are focused on performing a high volume of procedures, which creates a disincentive for them to refer patients to a clinical trial outside of their practice.
• Lengthy timeline to conduct a large, multicenter trial—Navigating regulatory barriers and overcoming difficulties in recruiting the right group of patients to participate in a study can lead to substantial delays in conducting a trial (see Chapter 3). In the case of OAT, the timeline was 10 years.