Efficacy and Safety of Intensive Blood Pressure Therapy Using RMST – Insights from the SPRINT Trial

Restricted mean survival time (RMST) has limited current use in cardiovascular clinical trials. It’s considered a translational statistic – a summary measure that can be readily understood by clinicians and patients. RMST, the area under the Kaplan-Meier curve, provides an intuitive method to assess the impact of an intervention. It complements current methods by quantifying treatment-related gains [days gained from reduction of major adverse cardiovascular events (MACE)] and losses [days lost from increase in serious adverse events (SAE)] within a pre-defined timeframe (1).

We compared differences in event-free time between intensive (IT, <120 mmHg) and standard (ST, <140 mmHg) blood pressure therapy in Systolic Blood Pressure Intervention Trial (SPRINT) (2). The composite efficacy outcome was nonfatal myocardial infarction, other acute coronary syndromes, stroke, heart failure, or cardiovascular death. The 6-point (hypotension, syncope, electrolyte abnormality, bradycardia, injurious falls or acute kidney injury) composite safety outcome were SAEs or resulted in emergency room visits from any of the 6 conditions (3). Complete definitions of all individual components are at: https://www.sprinttrial.org/public/Protocol_Current.pdf. RMST was calculated from baseline to 4.2 years (end of study follow-up) and analyzed using strmst2 command in STATA Version 15 (StataCorp, College Station, TX) (4).

At 4.2 years, IT participants had a statistically significant 13.8 (95% CI: 3.9 to 23.6, P=0.006) more MACE-free days compared to ST participants (Figure 1A); IT participants had 1441.9 MACE-free days (95% CI:1435.3–1448.5) while the ST participants had 1428.1 MACE-free days (95% CI: 1420.9–1435.3). At 4.2 years, IT participants had 37.7 fewer SAE-free days (95% CI: −54.2 to −21.1, P=0.0001) compared to ST participants (Figure 1A); IT participants had 1370.9 SAE-free days (95% CI: 1358.7–1383.3) and ST participants had 1408.6 SAE-free days (95% CI: 1397.5–1419.7.

Figure 1.

A. Restricted Mean Survival Analysis Demonstrating Difference in Event-Free Days Gained or Lost between Intensive and Standard Blood Pressure in SPRINT Trial Participants. B. Cumulative Hazard, Absolute Risk, and Number Needed to Harm for 6-Point Composite Safety Outcome

For the efficacy outcome the absolute risk reduction with IT therapy was 1.62% (95% CI: 0.65% to 2.6%) with a number needed to treat (NNT) of 62 over 4.2 years. The hazard ratio was 0.75 (95% CI: 0.64–0.89) compared to ST. For the safety outcome, the increase in absolute risk with IT therapy was 3.23% (95% CI: 1.7% - 4.7%) with a number needed to harm (NNH) of 31 over 4.2 years. The hazard ratio was 1.25 (95% CI: 1.13–1.39) compared to ST (Figure 1B).

We demonstrated that in the SPRINT trial, IT was associated with a net gain of 2 weeks of MACE-free days at a cost of having about 5 weeks of fewer SAE-free days. Moreover, by providing an intuitive statistic of benefit and harm RMST has the potential to improve the shared decision-making process between patients and clinicians, in concert with current statistics (hazard ratio, absolute risk, and NNT/NNH), in determining optimal blood pressure intensity (1). Therefore, RMST may be particularly useful in older, multimorbid, adults where balancing disease-centered and patient-centered outcomes is of great importance.

A limitation of this analysis is that MACE and SAEs, as defined in SPRINT, are not equivalent outcomes. Application of the RMST findings requires subjective weighting of the importance of avoiding MACE vs SAEs at the patient level. At the population level, it is also important to ensure that no unnecessary increase in MACE outcomes occurs due to misinterpretation of findings from this study.

In conclusion, RMST – a translational statistic - demonstrated intensive BP therapy recipients gained 14 MACE-free days but lost 38 SAE-free days. These findings should be taken together with standard measures of treatment effect during discussion of optimal blood pressure treatment intensity.