Author + information
- Christopher M. O’Connor, MD, Editor-in-Chief, 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.
In 1984, I conducted my first n-of-1 clinical trial in which I stumbled into a patient with the diagnosis of Whipple’s disease of the lung presenting with pulmonary hypertension. After reviewing the limited reports at the time and with the consent of the patient and institution, I initiated a long-term course of doxycycline. Over the subsequent 6 months, the patient’s symptoms improved, including dyspnea and echocardiographic parameters of pulmonary hypertension. I presented this case at the American College of Physicians. Thirty-five years later, I conducted another n-of-1 clinical trial, perhaps one of several hundred over the course of my career. In one of my patients, an 84-year-old female who had been hospitalized multiple times over the previous 6 months with heart failure, preserved ejection fraction, diabetes, and unable to tolerate most medications, I initiated sodium glucose co-transporter (SGLT2) inhibitor for diabetes control (1). This therapy resulted in a reduction in heart failure symptoms, weight, dyspnea and improvement in glycemic control. The patient moved from an initial state of worse quality of life through the initiation of therapy to a subsequent state of improved quality of life. She remained out of the hospital for 1 year. This experience stimulated my interest in re-evaluating the n-of-1 clinical trial experience.
Clearly, there is much to learn from these experiences of the clinicians in their day-to-day treatment decisions. We can improve the rigor of these observations through several important methods that we have learned from large-scale randomized controlled clinical trials. The problem with the n-of-1 clinical trial is that effectiveness may be overestimated because of 3 different possibilities, as follows:
1. A patient can spontaneously recover coincident with treatment. This is well known to occur in chronic illnesses.
2. We know that the placebo effect occurs and that it can be as much as 30% or more of the benefit.
3. Treatment may be initiated during the waxing and waning of symptoms of a chronic condition, and it is possible that the return to baseline was spontaneous and “a regression to the mean” that was independent of the treatment provided.
Many of us are familiar with the single-patient clinical trial involving the internal mammary artery ligation for coronary insufficiency that was published in the paper by Dr. Ralph Adams (2). In that n-of-1 clinical trial, the patient presented with coronary insufficiency with precordial pain. Internal mammary ligation and alteration of the circulation were proposed in hopes of reducing pain and had been widely adopted at that time in cardiovascular medicine. The patient underwent surgery with incisions made in which each internal mammary artery was exposed; a ligature was wrapped around each artery but not tied. The patient was awakened from anesthesia and reported that he was free of pain and had no pain since the operation for the subsequent 48 h. After the short follow-up period, the internal mammary arteries were tied. The patient continued to be pain free. This case was one of the first examples of the internal mammary operation that might have had a strong placebo effect, thus, the importance of formalizing the criteria of n-of-1 clinical trials. Perhaps one should consider, if possible, 3 important characteristics of the proposed investigation, as follows (3):
1. Randomization would be optimal because it minimizes systematic bias that can occur related to the initiation of a treatment.
2. Blinding, if possible, would also improve observer-induced biases. If possible, both the patient and the physician would be blind to treatment assignment. However, this requires a greater level of sophistication in the staff, usually involving a pharmacist and a nurse to help coordinate the investigation.
3. Quantitating the outcomes and the evaluation of the efficacy of the treatment are important features of a single-patient trial.
With this said, several investigators across the globe have begun formalizing the n-of-1 clinical trial service and conducting multiple n-of-1 clinical trials with the rigor of large-scale clinical trials. In a report from Guyatt (4) at McMaster University of the first 42 trials done at the center, 29 gave definitive results.
Thus, I call upon our heart failure community to formalize the thousands of single-patient trials that we conduct in clinical practice everyday. I ask you to try to provide more rigor in conducting these single-patient trials and to share these experiences with our patients and professional community—if and only if no formal randomized trial or registry is available.
- 2019 American College of Cardiology Foundation