42 clinical centers participated, over 8,500 elderly hypertensive patients enrolled within 1 year, with a loss to follow-up rate of only 2%…… Behind these numbers, how did the STEP researchers ensure uniformity across clinical centers, how did they coordinate, and how were they able to still achieve NEJM publication after similar blood pressure studies like ACCORD and SPRINT? (See “China’s STEP Study Tops NEJM: Enhanced Blood Pressure Control Reduces Cardiovascular Events in Elderly Hypertensive Patients | Wei Meng’s Commentary”)?
With these questions in mind, NEJM Medical Frontier recently interviewed Professor Cai Jun, who leads the STEP study at Fuwai Hospital.
Professor Cai Jun presents at ESC 2021
Please share your experiences regarding the article published in the New England Journal of Medicine.
The acceptance of our paper by the New England Journal of Medicine can be summarized in two reasons. The first is that our study addresses a particularly important issue, which I will elaborate on later. The second reason is that the STEP trial is a high-quality, nationwide multi-center randomized controlled trial. By solving a particularly important problem through high-quality randomized controlled research, it is only natural that the research paper would be accepted by the New England Journal of Medicine.
Previously, there were international randomized controlled studies on enhanced blood pressure control such as SPRINT and ACCORD. Could you discuss what shortcomings in these studies prompted you to conduct the STEP study?
The SPRINT and ACCORD trials target different populations than our STEP study. SPRINT focuses on hypertensive patients with high cardiovascular risk factors, while ACCORD targets patients with diabetes and hypertension. The ACCORD study enrolled 4,733 patients but failed to yield positive results. The SPRINT trial enrolled 9,361 patients but learned from the ACCORD trial’s lessons by excluding patients with diabetes and stroke.
Moreover, the SPRINT trial has some flaws: First, to achieve lower blood pressure target values, over 50% of patients were on more than three antihypertensive medications, which raises potential side effects and cost-effectiveness issues; second, excessively low blood pressure increases the risk of kidney damage; third, the blood pressure measurement methods used in the trial do not align with clinical practice, limiting its applicability.
Neither of these studies specifically targeted elderly hypertensive patients. A key issue that hypertension experts have been concerned about for nearly 30 years is what level blood pressure should be lowered to in elderly hypertensive patients, which lacks evidence-based medical data. Previous studies have shown that lowering blood pressure in elderly hypertensive patients to below 150 mmHg can improve prognosis, but whether lowering it further is meaningful remains unclear, as there is currently no related data, meaning there has been a lack of target blood pressure values for elderly hypertension.
Since neither of these trials specifically targeted hypertensive patients aged 60 to 80, and this patient demographic constitutes a significant portion of the hypertensive population, as China’s aging population increases, the number of these patients will continue to grow. The impact of the research results on this patient group is immense, underscoring the study’s importance.
How do you ensure a high level of quality in completing the STEP trial?
To ensure high-level and high-quality completion of clinical trials, there are several key considerations:
First, the importance of the research question must be ensured. This point has been discussed previously, so I will not elaborate further.
Second, when formulating patient inclusion criteria, comprehensive consideration is necessary. For instance, in the STEP trial, to ensure the representativeness of enrolled patients, those with diabetes were included. However, patients with a history of stroke were excluded. The reason is that in China, the annual recurrence rate of ischemic stroke is as high as 17.7%. Including stroke patients would lead to significant bias in our results.
Third, in setting blood pressure target values, we balanced scientific rigor with operational feasibility. Based on literature and domestic and international guidelines, we set the target value for the enhanced blood pressure control group at 110-130 mmHg and for the standard control group at 130-150 mmHg. This is a scientific consideration.
We initially considered dividing participants into three groups with target values set at <120 mmHg, 120-130 mmHg, and 130-150 mmHg. However, due to the large fluctuations in blood pressure in the elderly, it is challenging to maintain blood pressure within the target range. From an operational perspective, dividing into two groups is the most ideal to ensure the smooth implementation of the study. Additionally, based on experiences from the SPRINT trial, if the target value is set at <120 mmHg, patients would need to take an average of three antihypertensive medications, which could lead to poor adherence. Furthermore, our trial involves multiple research units and researchers, with varying levels of expertise across institutions.
Professor Cai Jun leads a project discussion meeting
It has been proven that in the STEP trial, the enhanced treatment group averaged 1.9 antihypertensive medications, while the standard treatment group averaged 1.5. The average blood pressure in the enhanced treatment group was 127.5 mmHg, while in the standard treatment group it was 135.3 mmHg, with high patient adherence, achieving the study’s expectations.
Fourth, regarding blood pressure measurement, we considered three main issues. To ensure our data is of reference value, we abandoned the blood pressure measurement method established by the SPRINT trial and used conventional office blood pressure and home self-measured blood pressure. Our trial found that the office blood pressure and self-measured blood pressure were very close, with only a 3 mmHg difference.
To ensure patients could consistently self-measure their blood pressure, we provided patients with blood pressure monitors equipped with Bluetooth and APP functionality for free. This was a significant highlight of the study. The original goal was to supervise patients to measure their blood pressure regularly to prevent incomplete data. The result was that using the Internet+ model increased patient engagement; researchers could monitor patients’ blood pressure and medication adherence while ensuring the accuracy, completeness, and consistency of data collection. As patients’ blood pressure data was uploaded to the platform in real-time, we could monitor patients’ blood pressure and provide timely feedback, ensuring the effectiveness of the trial. This also significantly reduced the loss to follow-up rate: the STEP trial’s loss to follow-up rate was only 2.7%, far lower than that of the SPRINT trial and others.
Fifth, to ensure the smooth conduct of the trial, we conducted training for participating researchers. Through training, we improved the capabilities of all participating researchers, laying a solid foundation for the successful completion of this project and cultivating a group of clinical research talents in our country.
Professor Cai Jun provides in-depth guidance on-site for the trial
The results of the STEP trial found that the risk of endpoints such as stroke or acute coronary syndrome decreased in the enhanced blood pressure control group, but there was no significant difference in all-cause mortality, and the incidence of adverse events such as acute kidney injury or renal failure also did not significantly increase. This result differs from the SPRINT study; could you analyze this in depth?
The STEP trial results indicated that compared to the standard blood pressure control group, the risk of cardiovascular death in the enhanced blood pressure control group was significantly reduced by 28%, the risk of stroke decreased by 33%, the risk of acute coronary syndrome decreased by 33%, and the risk of heart failure decreased by 73%. Additionally, there were no significant differences in safety and kidney outcomes between the two groups. These results suggest that enhanced blood pressure control has significant value and could potentially change treatment guidelines for elderly hypertension.
As for the lack of difference in all-cause mortality, our post-hoc analysis found that compared to the mortality rate of elderly hypertensive patients in China, the cardiovascular mortality rates in both the enhanced and standard blood pressure control groups of the STEP trial decreased. However, since cardiovascular mortality comprises a small proportion of all-cause mortality, the overall all-cause mortality rates of the two groups did not show significant differences.
The incidence of acute kidney injury or renal failure in the enhanced blood pressure control group of the STEP trial did not increase, whereas the SPRINT trial showed an elevated risk. The main reason for this is that the target blood pressure in the STEP trial was higher than that in SPRINT. It is well known that excessive drops in blood pressure can affect renal blood supply. Additionally, in the SPRINT trial, patients in the enhanced treatment group averaged three antihypertensive medications, which could also contribute to the higher incidence of renal adverse events.
This research undoubtedly benefits millions of hypertensive patients in our country. What other questions do you think this study has not answered, and what are your future research directions?
This study was conducted over a long period, collecting a large amount of data. In addition to the completion of the main data analysis, there are many other aspects of data that can be analyzed. For example, in our study, there were over 2,000 patients who used only angiotensin receptor blockers (ARBs) and calcium channel blockers (CCBs), and we can analyze whether these two drugs have different impacts on target organs and which antihypertensive medication is more suitable for the target population.
Furthermore, our trial adopted an Internet+ model, collecting a large amount of blood pressure data, so in the future, we can use big data and artificial intelligence to develop risk prediction models to study which elderly individuals are prone to stroke and which are prone to myocardial infarction.
Additionally, issues regarding blood pressure targets for hypertension with comorbidities are also of interest. For example, the ACCORD trial found that enhanced blood pressure control did not yield benefits for diabetic patients, but the patient population was too small; thus, if we increase the number of enrolled patients, can we obtain positive results? Other areas of focus for my future research include target blood pressure values post-stroke and pre-hypertension.
Author Introduction
Professor Cai Jun, Chief Physician at Fuwai Hospital, Chinese Academy of Medical Sciences, Professor, Doctoral Supervisor, currently serves as Assistant Dean, Director of the Hypertension Center, and Director of the Hypertension Ward. He has long worked on the front lines of cardiovascular clinical practice, focusing on exploring the pathogenesis of hypertension and effective prevention and treatment methods. He serves as the Chair of the Hypertension Professional Committee of the Cross-Strait Medical and Health Exchange Association of the National Health Commission, President of the Grassroots Cardiovascular Disease Branch of the Chinese Society of Cardiothoracic and Vascular Anesthesia, and a member and Deputy Leader of the Hypertension Group of the Cardiovascular Disease Branch of the Chinese Medical Association. He has led over ten projects including the Ministry of Science and Technology’s 973 Program and key projects of the National Natural Science Foundation, publishing over 40 SCI articles in NEJM, Circulation, Hypertension, etc., as the first author or corresponding author. He has received numerous accolades, including the National Outstanding Youth Fund, the Ministry of Science and Technology’s Young and Middle-aged Science and Technology Innovation Leading Talent Award, the Ministry of Education’s New Century Excellent Talent Award, the National Natural Science Foundation’s Excellent Young Fund, the China Youth Science and Technology Award, and the Mao Yisheng Youth Science and Technology Award.
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