Purpose: The purpose of the study was to determine whether treating blood pressure to a target systolic pressure of less than 120 mm Hg is superior to treating to less than 140 mm Hg, which was the commonly recommended target at the time that the SPRINT trial was conducted.
Background: High blood pressure is a major public health problem because it is highly prevalent, affecting 1 in 3 American adults, and because it is an important risk factor for health problems such as heart attack, heart failure, stroke, chronic kidney disease, and cognitive function decline.
When the SPRINT study was designed, there was consensus in the medical field that reducing elevated systolic blood pressure benefited patients by preventing cardiovascular death and complications. But the benefits and potential side effects of treating to a systolic blood pressure well below 140 mm Hg had not been well established.
Design: This was an unmasked, open-label randomized controlled multicenter clinical trial.
Primary Outcomes: Primary outcomes included heart attack, non-myocardial infarction acute coronary syndrome, heart failure, cardiovascular death, and stroke.
Secondary Outcomes: Secondary outcomes included all-cause mortality, decline in kidney function or development of end-stage renal disease, incident dementia, decline in cognitive function, and small vessel cerebral ischemic disease. The main secondary kidney outcome, restricted to the chronic kidney disease subgroup, is a composite of a 50 percent decrease in estimated glomerular filtration rate from baseline or incident end-stage renal disease.
Participants: The study included data from 9,361 adults age 50 or older with systolic blood pressure of 130 mm Hg or higher and at least one additional cardiovascular disease risk factor. Participants included men and women, members of racial/ethnic minority groups, and older adults; 25 percent of participants were over the age of 75. Participants with diabetes, prior stroke, or polycystic kidney disease were excluded. A breakdown of participant demographics as well as a complete list of inclusion and exclusion criteria can be found in the published SPRINT design paper.
Enrollment: Participant enrollment occurred between 2010 and 2013 at 102 sites in the United States, including Puerto Rico.
Treatment Arms: The protocol for the intensive treatment group was designed to achieve a systolic blood pressure target of less than 120 mm Hg. On average, this group received three medicines to achieve the target. The protocol for the comparison treatment group was designed to achieve a systolic blood pressure target of less than 140 mm Hg. On average, this group received two medicines to achieve the target. Medicines from the major classes of antihypertensive agents were provided by SPRINT at no cost to the participants. SPRINT investigators could also choose to administer other antihypertensive medicines that were not provided by the trial. The SPRINT formulary is presented in Table 2 of the published SPRINT design paper. The treatment algorithms for both arms of the trial are also available in Figures 3 and 4 of the SPRINT design paper.
Study Results: Compared with managing systolic blood pressure to a target of less than 140 mm Hg, intensive management of systolic blood pressure to a target of less than 120 mm Hg reduced rates of complications of high blood pressure—including heart attacks, heart failure, and stroke—by 25 percent and lowered the risk of death by 27 percent. Early analyses indicated that the results are consistent for the overall study population. Separate analyses showed that the more intensive treatment also specifically benefited participants age 75 and older, patients with chronic kidney disease, and various racial and ethnic subgroups. The study successfully retained a majority of the randomized cohort. Researchers maintain a complete list of publications from the initial study and ancillary analyses on the SPRINT trial website.
Action Taken: The study was monitored by a Data Safety Monitoring Board (DSMB), which performed interim analyses of study results to look for any indication that one treatment arm was superior to the other arm. Because of the superior benefits of the more intensive blood pressure treatment intervention on the primary outcome and on total mortality, the DSMB recommended notifying the study investigators and communicating these important results to participants, investigators, and the public. The National Heart, Lung, and Blood Institute (NHLBI) concurred with this assessment and accordingly ended the blood pressure intervention of SPRINT, notified trial participants and investigators, and reported these initial findings publicly.
Additional Information: For other study-design considerations such as power and event-rate assumptions, please see the SPRINT design paper.
Q1: Why was the SPRINT blood pressure intervention stopped early?
A: The study was monitored by an independent Data and Safety Monitoring Board (DSMB) that performed interim analyses of study results and adverse events to look for any indication that one treatment arm was superior to the other arm. As the study progressed, it became clear that, compared with a systolic blood pressure target of less than 140 mm Hg, intensive management of systolic blood pressure to a target of less than 120 mm Hg significantly reduced rates of complications of high blood pressure—including heart attacks, heart failure, and stroke—and lowered the risk of death.
In view of the superior benefits of the more intensive blood pressure treatment intervention, the DSMB recommended communicating these results to study participants, investigators, and the public. NHLBI accepted this recommendation and ended the blood pressure intervention of the SPRINT study in advance of the original trial end date. The Institute believed that it would not be ethical to withhold these results from standard care group participants and their healthcare providers.
Other components of the study include SPRINT-MIND, which is examining whether the lower blood pressure target will reduce the incidence of dementia, slow declines in cognitive function, and result in less cerebral small vessel disease as shown on magnetic resonance imaging (MRI) compared with the standard target. Data analysis continues for the SPRINT-MIND study as well as on kidney-related outcomes.
In addition, the National Institute on Aging (NIA) is funding the SPRINT researchers to conduct a follow-up study of SPRINT participants for one additional visit to test whether the incidence of all-cause dementia and mild cognitive impairment is lower in participants in the intensive arm compared with the standard arm. This study is called The SPRINT Alzheimer’s, Seniors, and Kidney Study (SPRINT ASK). The results of the SPRINT-MIND and SPRINT ASK studies will be combined and will likely be available in 2019.
Q2: What did the clinical protocol include to ensure the greatest benefit and least harm to participants undergoing the intensive treatment arm of the SPRINT trial?
A: Participant safety is paramount at every stage of the clinical trial process: designing the protocol, implementing the intervention, and monitoring for side effects of the intervention. In addition, the SPRINT protocol underwent multiple layers of review and approval, including consideration by approximately 50 sites’ Institutional Review Boards (IRBs) and the trial’s DSMB, which were independent of the NHLBI.
Participant safety was carefully monitored. The protocol required regular monitoring for serious adverse events, the collection and monitoring of laboratory measures, a procedure for immediately reporting clinical safety alerts, physical exams, and a standardized protocol for measuring sitting and standing blood pressure.
Q3: This study has a component (SPRINT-MIND) that is examining the risk of dementia with different degrees of blood pressure control. What is the status of this part of the study?
A: The SPRINT Memory and Cognition in Decreased Hypertension (MIND) study is comparing the two blood pressure targets for their impact on cognitive function and dementia. Researchers conducted dementia testing in all SPRINT participants and additional cognitive function testing and magnetic resonance imaging (MRI) scans of the brain in a subset of participants. Researchers continue to analyze the results of this testing and are conducting one additional visit with SPRINT participants to collect final cognitive assessments. These consolidated cognitive findings are expected in 2019.
Q4: Are there any other unanswered questions about the benefits of intensive treatment of high blood pressure that remain for the SPRINT trial to address?
A: Yes. Because the intervention component of SPRINT ended early, there are two important questions that still remain to be addressed: the effects of the two blood pressure targets on dementia and cognitive functioning (SPRINT-MIND), and their effects on decline in kidney function.
SPRINT-MIND is examining whether the lower blood pressure target will reduce the incidence of dementia, slow declines in cognitive function, and result in less cerebral small vessel disease compared to the standard target, as shown on MRI. Data analyses are ongoing for these questions.
Q5: How are NHLBI-supported SPRINT data being used to fuel scientific discovery?
A: As part of an NHLBI-supported data challenge launched in 2016, nearly 150 teams submitted new scientific or clinical discoveries based on their analysis of SPRINT data. Visit the SPRINT trial website for regular updates of new findings from the study data.
Q6: This study was also designed to measure the benefits of a lower blood pressure target for patients with chronic kidney disease. Is there benefit for this population as well?
A: Yes. At the beginning of the trial, 28 percent of participants had chronic kidney disease. As with the overall study population, the trial results for patients with chronic kidney disease showed significantly reduced rates of high blood pressure complications and a lower risk of death. Some complications were more common among patients with kidney disease, but the results favored more intensive treatment overall.
Q7: Several years ago, the ACCORD study, also funded by NHLBI, concluded that intensive blood pressure lowering was not indicated for people with diabetes. Do these results contradict those findings?
A: The ACCORD blood pressure study had a different population, focusing primarily on adults with type 2 diabetes, and no participants were older than 79. The SPRINT study was designed to complement the ACCORD study. It did not include individuals with diabetes.
The ACCORD blood pressure study was smaller than the SPRINT trial and looked at the impact of control of blood pressure and blood sugar. While the ACCORD study failed to show a benefit of lower blood pressure in patients with diabetes, the apparent inconsistency with the SPRINT trial may reflect these and other differences in how the two studies were designed.
Q8: Were there differences in the adverse events observed between the two treatment groups?
A: Safety and efficacy data were monitored throughout the trial by an independent DSMB. With any intervention, some adverse effects are expected. Sometimes there are unanticipated adverse effects. The DSMB did not recommend changes to the protocol or informed consent because of safety concerns at any point in the study.
During the trial, investigators monitored the frequency of certain events that could be related to the study intervention. These included hospitalizations and emergency department visits for kidney failure or kidney damage, falls, fainting, a slow heart rate, low blood pressure, and imbalances in the body’s electrolytes. These expected events are reported in the primary outcome paper. NHLBI reviewed these expected events in making its decision on whether to accept the DSMB’s decision and concluded that the benefits of treating high blood pressure to less than 120 mm Hg outweighed any harm. The cost-benefit analysis published in 2017 also concluded that the benefits of treating to the lower goal outweighed the harms.
Q9: What role did private companies play in implementing this trial and what medicines were used in the trial?
A: No private companies funded the SPRINT trial, and no private company was involved in the development of the protocol.
The SPRINT protocol was finalized in 2010. In January 2013, NHLBI signed an agreement for medicine donations with one company, Takeda Pharmaceuticals International, Inc. Takeda contributed two study medicines (azilsartan alone and azilsartan with chlorthalidone), which were two in a formulary of many antihypertensive medicines. Azilsartan is an angiotensin II receptor antagonist. Chlorthalidone is a commonly prescribed diuretic. Approximately five percent of participants took one of these donated medicines.
Arbor Pharmaceuticals, LLC, subsequently assumed the licensing for the Takeda drugs and thus has participated in donating these antihypertensive medicines to SPRINT. Various classes of standard antihypertensive medicines were included in the formulary for the SPRINT trial, including diuretics, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers, calcium channel blockers, and beta blockers, among others. Many SPRINT blood pressure medicines were generics.
Information regarding the drug formulary supporting the implementation of this trial can be found in the published SPRINT design paper.
Q10: What did the SPRINT study cost to conduct?
A: When the study is totally completed, the cost will be approximately $157 million over eight years.
Q11: For whom are these results applicable?
A: In the SPRINT population of non-diabetic individuals age 50 and older, the benefits of treatment to the intensive blood pressure goal of less than 120 mm Hg appear to exceed the potential for harm, regardless of patient gender, race, ethnicity, or age.
Q12: Why do national guidelines set a different target blood pressure than what this study suggests?
A: The high blood pressure guidelines that the American College of Cardiology (ACC) and the American Heart Association (AHA) published in November 2017 take into account decades of research on the management of high blood pressure. The SPRINT trial provided important evidence about the safety and effectiveness of following a more intensive treatment target in high-risk individuals. Its findings helped influence a key part of the new guidelines, but were only one of many studies that the experts considered in developing their guidelines. Read the new guidelines in the Journal of American College of Cardiology or Hypertension.
Q13: What should doctors tell their patients in light of the SPRINT trial results?
A: For many high-risk patients, the SPRINT trial confirmed the benefits of lowering blood pressure beyond the previously recommended target of less than 140 mm Hg and beyond the new ACC/AHA guidelines’ definition of high blood pressure: less than 130/80 mm Hg. When discussing the best treatment approach for individual patients, it will be important for providers to take each patient’s complete health profile into consideration.
The results of the SPRINT study reaffirm the critical importance of blood pressure control as the best approach to reduce complications of high blood pressure like heart attacks and strokes. Patients’ individual medical histories, including the number of medicines they are taking to control their high blood pressure and whether they have other chronic conditions, will also ultimately determine the blood pressure treatment goals that patients set with their providers.
Q14: Is lowering blood pressure to this level safe, especially in older adults?
A: The SPRINT study suggests that the lower blood pressure target of less than 120 mm Hg is generally well tolerated in all age groups studied: non-diabetic adults age 50 and older. A separate analysis focused on adults age 75 and older confirmed that, as with the overall study population, those with high blood pressure benefit from the lower pressure target. About three-fourths of the U.S. population age 75 and older have high blood pressure.
Q15: Besides taking blood pressure medicines, what are some other steps patients can take to control blood pressure?
A: In addition to taking medicines to reduce high blood pressure, patients can take other steps to prevent the long-term problems high blood pressure can cause. They can follow healthy lifestyle habits such as choosing a heart-healthy eating pattern including the DASH eating plan, being physically active, maintaining a healthy weight, quitting smoking, and managing stress. A healthy lifestyle can also help prevent high blood pressure in children and teens.
Q16: What’s a good source of additional information on high blood pressure?
Q17: Where are the results of this study published?
A: In 2015, the SPRINT Research Group published its results in the New England Journal of Medicine. Researchers continue to analyze SPRINT data. Researchers maintain a complete list of publications based on data from the study on the SPRINT trial website.
Q18: Are the New England Journal of Medicine article and related supplementary materials freely available to all at the journal’s website?
A: The New England Journal of Medicine has agreed to make the article and the data tables freely available in the public domain.