Time in Therapeutic Range: Redefining "Optimal" Blood Pressure Control

George Bakris, MD; Hillel Sternlicht, MD


J Am Coll Cardiol. 2021;77(10):1300-1301. 

As our understanding of primary hypertension has deepened over the last 5 decades, researchers have sought more sophisticated ways to prognosticate the disease. Concerning treatment, blood pressure (BP) targets are now derived from outcomes of multiyear trials enrolling thousands of participants and identifying cohorts of interest via multivariate risk calculators. However, BP values are generally obtained by static readings in an office setting, regardless of the measurement protocol. Data from clinical trials and recent epidemiological studies demonstrate that masked hypertension, that is, readings above the recommended goals outside the office setting, has a mortality rate and affects kidney disease progression like poorly controlled hypertension.[1] Moreover, masked hypertension may interfere with clinical trial outcome interpretation.[2]

Given that BP control must be maintained over many years to realize the cardiorenal benefits, there has been increasing emphasis on characterizing BP control over time. Moreover, meta-analyses have primarily supported the independent association between greater visit-to-visit variability in systolic or diastolic BP and worse cardiovascular (CV) and renal outcomes.[3,4] Fluctuations in systolic BP of 5 to 10 mm Hg portend higher all-cause mortality than those with more consistent clinic readings.[5]

In this issue of the Journal, Fatani et al.[6] delve into the nascent field of time in therapeutic range (TTR) whereby they seek to quantify the magnitude of the difference between intended and measured BP values (BP variability) as a function of the duration of time it persists. A correlation between an individual's time in (systolic) target range (e.g., 0% to 25%, 25% to 50%, >50%) and major adverse cardiovascular events (MACE) was sought. Data were drawn from SPRINT (Systolic Blood Pressure Intervention Trial), an open-label, randomized controlled trial comparing the CV effects of a systolic BP goal of ≤120 versus ≤140 mm Hg on CV outcomes. Only those with hypertension greater than a 15% 10-year CV risk score and no history of diabetes or stroke were eligible. At the time of each study visit, BP was taken in triplicate via an automated unattended monitor. Fatani et al. calculated TTR during months 0 to 3 of SPRINT with subsequent surveillance for MACE. Target ranges, such as 110 to 130 mm Hg, replaced target values (e.g., 120 mm Hg). SPRINT participants were excluded in this analysis if they achieved their goal BP before randomization. Ultimately, two-thirds of the 9,400 SPRINT participants, one-third of whom were women, were evaluated over a 3.3-year follow-up period.

Upon dividing the cohort into quartiles, the mean systolic BP was 140 mm Hg in those achieving a TTR of 0% to 25%. Mean systolic BP was 124 mm Hg in the 75% to 100% TTR group. Participants required 2 to 3 antihypertensives to achieve their BP goal, but those achieving greater TTR did not need more numerous agents. Greater time in the target range predicted a lower risk of MACE, irrespective of the BP goal. This benefit persisted after adjustment for mean BP, demographic factors, medical history, and BP variability. There was no relationship between the duration of time within the therapeutic window and adverse events such as hypotension, syncope, falls, or kidney injury. The authors note that for each 1-SD increase in TTR, there was a decreased MACE risk after adjustment for age, sex, and race. TTR remained associated with MACE with further adjustment for mean systolic BP. It is important to note that TTR also remained associated with major adverse cardiovascular events for those with mean systolic BP at or below target.

These findings amplify the work of Doumas et al.,[7] who analyzed about 700,000 Veterans Administration patients over 10 years. Using a similar methodology, Doumas et al. noted that TTR of BP was a strong predictor of adverse events and survival.[7] When these 2 papers are considered in concert, the conclusion of Fatani et al.[6] that "time in target range provides incremental value beyond mean systolic blood pressure" is indeed justifiable.

Although the net benefit may appear modest—a 22% relative risk reduction per standard deviation increase in time in the target range—it is meaningful given the small sample size and brief follow-up interval (3.3 years). Conversely, individuals who are adherent to their medication regimens and capable of achieving their guideline BP in a short, reasonable period would gain the most from the prognostic information this paper supplies.

The contribution of Fatani et al.[6] to the field resonates within the clinic setting as well. It deepens our understanding of the benchmarks required to designate a patient's BP as "controlled" and offers complete criteria to date for (prognostically) classifying BP values as "optimal." It reminds the physician that the patient's BP on the visit day should be compared to prior encounters and those measured during the initial 3 or 4 appointments. These data are also a clarion call for home BP monitoring and, by extension, the patient's ongoing responsibility for his/her care. If performed correctly, home BP monitoring is validated against the daytime values recorded by a 24-h ambulatory monitor.[8] Apart from 24-h monitors, home measurements remain the only reliable way to diagnose masked hypertension and BP variability. This publication suggests that patients would be well served to ask themselves not only, "What is my blood pressure?" but "What was my blood pressure?"