(For a list of Frequently Asked Questions click here.)
Purpose: To determine whether treating blood pressure to a target systolic pressure of <120 mm Hg is superior to treating to the commonly recommended target of <140 mm Hg.
Background: High blood pressure is a major public health problem because it is highly prevalent, affecting 1 in 3 American adults, and is an important risk factor for health problems including heart attack, heart failure, stroke, chronic kidney disease, and cognitive function decline.
When the SPRINT study was designed, there was general consensus in the medical field that reducing elevated systolic blood pressure benefits patients by preventing cardiovascular death and complications; yet the benefits and potential side effects of treating to a systolic blood pressure well below 140 mm Hg had not been well established.
Design: An unmasked, open-label randomized controlled multicenter clinical trial.
Primary Outcomes: Heart attack, non-myocardial infarction acute coronary syndrome, heart failure, cardiovascular death, and stroke.
Secondary Outcomes: 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% decrease in estimated glomerular filtration rate from baseline or incident end-stage renal disease.
Participants: 9,361 adults age 50 years 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, racial minorities, and the elderly (25% 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; Clinical Trials, 2014, Vol. 11(5) 532–546.
Enrollment: Participant enrollment occurred between 2010 and 2013 at 102 sites in the United States and Puerto Rico.
Treatment Arms: The protocol for the “Intensive” treatment group was designed to reach a systolic blood pressure target of <120 mm Hg. On average, this group received three medications to achieve the target. The protocol for the comparison treatment group was designed to reach a systolic blood pressure target of <140 mm Hg. On average, the comparison group received two medications to achieve the target. Medications from the major classes of antihypertensive agents were provided by SPRINT at no cost to the participants. SPRINT investigators could also select to administer other antihypertensive medications that were not provided by the trial. The SPRINT formulary is presented in Table 2 of the published SPRINT design paper; Clinical Trials, 2014, Vol. 11(5) 532–546. The treatment algorithms for both arms of the trial are also available in Figures 3 and 4 of the SPRINT design paper.
Initial Study Results: Intensive management of systolic blood pressure to a target of <120 mm Hg reduced rates of complications of high blood pressure (including heart attacks, heart failure, and stroke) by 30% and lowered the risk of death by almost 25% as compared to a systolic blood pressure target of <140 mm Hg. The interim analyses indicate these results are consistent for the overall study population. However, study results are still being analyzed particularly as they relate to subgroups. A primary outcome paper under development will describe the findings by a number of subgroups including women, African Americans, participants 75 years and older, and patients with chronic kidney disease.
The study successfully retained a majority of the randomized cohort. The investigators and NHLBI are working to complete the final analyses and publish the final results as expeditiously as possible. Notification regarding the publication of the final results and analyses for the blood pressure component of SPRINT will be available on the NHLBI website at www.nhlbi.nih.gov within the next few months.
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. Because of the superior benefits of the more intensive blood pressure treatment intervention on the primary outcome and on total mortality, the DSMB recommended un-blinding the study and communicating these important results to participants, investigators, and the public. NHLBI concurred with this assessment and accordingly ended the blood pressure intervention of SPRINT, notified trial participants and investigators, and has reported publicly these initial findings.
Additional Information: For other study design considerations such as power and event rate assumptions, please see the SPRINT design paper referenced above.
Q1: Why was the SPRINT blood pressure intervention stopped early?
- The study was monitored by an independent Data and Safety Monitoring Board (DSMB) which performed interim analyses of study results and adverse events to look for any indication that one treatment arm was superior to the other. As the study progressed, it became clear that intensive management of systolic blood pressure to a target of <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 as compared to a systolic blood pressure target of <140 mm Hg.
- In view of the superior benefits of the more intensive blood pressure treatment intervention, the DSMB recommended to communicate these results to study participants and investigators as well as to the public. The NHLBI accepted this recommendation and ended the blood pressure intervention of the SPRINT study in advance of the trial end date. The Institute believed that it would not be ethical to withhold these results from participants in the standard care group and their health care 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 the decline in cognitive function, and result in less cerebral small vessel disease (as shown on MRI) compared to those in the standard group. Data collection and analysis continue on the SPRINT-MIND study as well as on the kidney-related outcomes.
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?
- Participant safety is foremost at every stage of the clinical trial process—when designing the protocol, implementing the intervention, and monitoring for side effects of the intervention. In addition, the SPRINT protocol underwent multiple layers of protocol review and approvals, including by approximately 50 site Institutional Review Boards (IRBs) and the trial’s independent Data and Safety Monitoring Board, which is independent of the trial and of the NHLBI.
- Participant safety has been and continues to be carefully monitored in SPRINT. The protocol requires regular monitoring for serious adverse events, the collection and monitoring of laboratory measures, a procedure for immediately reporting clinical safety alerts, physical examinations, 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 will happen to this part of the study?
- When the blood pressure intervention portion of the SPRINT trial was stopped, only a small fraction of the outcome data for this important part of the SPRINT MIND study had been collected because most participants had not yet been in the trial four years. Although the blood pressure treatment component of the study is completed, the SPRINT protocol includes dementia testing in all participants, as well as cognitive function testing and magnetic resonance imaging (MRI) scans of the brain in a subset of participants. Since a small amount of this final data has been collected, we are asking participants to come back for clinic visits to collect this important data, which we anticipate should be accomplished by the summer of 2016. Therefore, results of the SPRINT MIND study are not yet available.
Q4: Are there any other unanswered questions about the benefits of intensive treatment of hypertension that remain for the SPRINT trial to address?
- Yes, because the intervention component of SPRINT ended early, there are two important questions that still remain to be addressed: 1) dementia and cognitive functioning (SPRINT-MIND), and 2) decline in kidney function.
- SPRINT-MIND is examining whether the lower blood pressure target will reduce the incidence of dementia, slow the decline in cognitive function, and result in less cerebral small vessel disease (as shown on MRI) compared to those in the standard group.
- Data collection and analysis continue on the SPRINT-MIND study as well as to assess kidney outcomes.
Q5: This study was also designed to answer the question for patients with chronic kidney disease, is there benefit for this population as well?
- Twenty eight percent of the participants had chronic kidney disease at the beginning of the trial. They are another important subgroup in the trial. The cardiovascular results for patients with chronic kidney disease are similar to those for the overall study population. Additional analysis and future SPRINT publications will address the significance of the findings for participants with kidney disease.
Q6: Several years ago the ACCORD study, also funded by NHLBI, concluded that intensive blood pressure lowering for diabetics was not indicated? Are these results contradictory?
- The ACCORD blood pressure study had a different population, since it focused primarily on adults with Type 2 diabetes and no patients were older than 79. The SPRINT study was designed to complement the ACCORD study and did not include individuals with diabetes.
- The ACCORD blood pressure study was smaller than the SPRINT trial and looked simultaneously 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 study design.
Q7: Were there differences in the adverse events observed between the two treatment groups?
- The safety and efficacy data from the trial was monitored throughout the trial by an independent Data and Safety Monitoring Board (DSMB). With any intervention, there are always some expected adverse effects, and sometimes there are unanticipated adverse effects. Throughout the study, the DSMB made no recommendations for protocol or informed consent changes due to safety concerns.
- During the trial there was monitoring for a specific list of expected events that could be related to the study intervention, including hospitalizations and emergency department visits for acute renal injury/failure, injurious falls, syncope, bradycardia, hypotension, and electrolyte disturbances. These expected events are reported in the primary outcome paper. The NHLBI reviewed these expected events in making its decision on whether to accept the DSMB’s decision and concluded that benefits of treating to <120 mm Hg outweighed harm.
To more fully understand the results of the study and their potential implications for clinical treatment decisions, further analyses are underway.
Q8: What role did private companies play in implementing this trial and what drugs were used in the trial?
- 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, and in January 2013, NHLBI signed an agreement for drug donations with one company, Takeda Pharmaceuticals International, Inc. Takeda Pharmaceuticals International, Inc. contributed two study medications (azilsartan alone and azilsartan combined with chlorthalidone), which were two in a formulary of many antihypertensive medications. Azilsartan is an angiotensin II receptor antagonist. Chlorthalidone is a commonly prescribed diuretic. Approximately 5% of participants were on one of these donated drugs.
- Arbor Pharmaceuticals LLC subsequently assumed the licensing for the Takeda drugs and thus has participated in donating these antihypertensive medications to SPRINT. Various classes of standard antihypertensive medications were included in the formulary for the SPRINT trial, including diuretics, ACE inhibitors, angiotensin receptor blockers, calcium channel blockers, and beta blockers, among others. At this time, most SPRINT blood pressure medications are generic.
- Information regarding the drug formulary supporting the implementation of this trial can be found in the published SPRINT design paper: Clinical Trials, 2014, Vol. 11(5) 532–546.
Q9: What did the SPRINT study cost to conduct?
- When the study is totally completed, the cost will be approximately $157 million over the eight years of the study.
Q10: For whom are these results applicable?
- In the SPRINT population of non-diabetic individuals age 50 years and older, the benefits of treatment to the intensive blood pressure goal of <120 mm Hg appear to exceed the potential for harm, regardless of gender, race/ethnicity, or age.
Q11: Why do national guidelines set a different target blood pressure than this study suggested is optimal? When will those guidelines be updated?
- These study findings are new and thus not reflected in the current guideline recommendations. Now that the blood pressure intervention results of the SPRINT trial are published, we believe that they will likely be considered in any future guideline efforts.
Q12: What should doctors tell their patients in light of the SPRINT trial results?
- Although it is well established that the treatment of hypertension prevents complications such as heart attacks, stroke, heart failure and death, there is concern that only half of all patients with hypertension have achieved adequate blood pressure control to the commonly recommended target of <140 mm Hg.
- The results of the SPRINT study re-affirm the critical importance of blood pressure control as the best approach to reduce the complications of hypertension such as heart attacks and strokes. While these findings are of great interest to physicians and their patients, the application of them in clinical practice will need to be informed by the treatment guidelines that experts will develop in light of these research results and in the context of other clinical evidence. Patients’ individual medical histories – including the number of medications they are taking to control their high blood pressure and whether they have other chronic conditions – will also ultimately determine the blood pressure treatment goal decision made by a health care provider and a patient.
Q13: Is lowering blood pressure to this level safe, especially in the elderly?
- The study suggests that the lower blood pressure target of <120 mm Hg is generally well tolerated in all age groups studied. In short, the benefits of the lower blood pressure goal appear to outweigh the risks.
Q14: Besides blood pressure medications, what are some other steps patients can take to control blood pressure?
- In addition to medications to reduce high blood pressure, patients can take other steps to prevent the long-term problems it can cause, especially a healthful diet that is rich in fruits and vegetables and low in salt or sodium, being physically active, maintaining a healthy weight, and not smoking. A healthful lifestyle can also help prevent high blood pressure in children and teens.
Q15: What’s a good source of additional information on high blood pressure?
- The NHLBI is a valuable source of information on high blood pressure. Visit http://www.nhlbi.nih.gov/health/health-topics/topics/hbp . For more information about the SPRINT trial, visit www.sprinttrial.org.
Q16: Where are the results of this study published?
- Results of the Systolic Blood Pressure Intervention Trial (SPRINT) appear in the current online issue of the New England Journal of Medicine: http://www.nejm.org/doi/full/10.1056/NEJMoa1511939
Q17: Is the NEJM article (and related supplementary materials) freely available to all at the Journal’s website?
- The NEJM has agreed to make the article and the data tables freely available in the public domain.