Abstract
Aims
Blood pressure (BP) control remains suboptimal among US patients with hypertension. Single-pill combination (SPC) therapies are commonly used to improve adherence; however, their effectiveness for achieving early and sustained intensive BP control is unclear.
Methods and results
We performed a post hoc analysis of Systolic Blood Pressure Intervention Trial (SPRINT) including 2736 participants propensity matched in a 1:2 ratio to compare effects of SPCs with equivalent multi-pill therapy. The estimated marginal odds of achieving target BP control were derived using generalized linear mixed models with repeated measures (LMMRMs). The association between time-updated SPC use and BP change in short- (≤6 months) and long-term (>6 months) follow-up was assessed with LMMRM and SPC * time interaction term. Multivariable Cox models evaluated the association of SPC use with cardiovascular events and serious adverse events (SAEs). Among SPRINT participants (n = 8623), 9.3% (n = 803) were prescribed SPC at baseline with greater use in the intensive vs. usual care group (5.79 vs. 3.90 per 100 person-months; P-diff < 0.001). Among matched pairs [SPC (n = 912); multi-pill therapy (n = 1824)], SPC use was associated with 22% increased likelihood of achieving target BP by 6 months [odds ratio (95% confidence interval), 1.22 (1.05, 1.42)]. Participants receiving SPCs (vs. multi-pills) experienced more rapid BP reduction in the first 6 months (−2.0 vs. −1.2 mmHg monthly change; P-diff < 0.001). Over long-term follow-up, participants using SPCs achieved significantly lower SBP at each time point. The risk of the primary CV composite endpoint and SAEs were not significantly different between groups.
Conclusion
Single-pill combination use resulted in greater likelihood of achieving target BP control and more rapid, sustained BP reduction without an increase in SAEs.
Keywords: Hypertension, Single-pill combination, SPRINT, Blood pressure control
Lay summary
This study found that blood pressure medications that combine two or more drugs in a single pill help patients achieve blood pressure control faster and more effectively than taking the same medications as separate pills.
Graphical Abstract
Introduction
The Systolic Blood Pressure Intervention Trial (SPRINT) demonstrated that intensive blood pressure (BP) control among patients with hypertension substantially lowered the risk of cardiovascular (CV) outcomes, prompting intensification of BP goals in contemporary guidelines.1-3 In the years since SPRINT’s original publication, achieving BP control in the USA has been highlighted as a public health imperative, motivating the Surgeon General’s Call to Action to Control Hypertension in 2020 and serving as a key component of the Million Hearts Initiative.4,5 If achieved, widespread adoption of intensive BP control has the potential to avert 107 500 deaths per year, ~20% of the annual CV mortality rate.6 This need is magnified globally, with hypertension-related deaths among older adults increasing by over 50% from 1990 to 2019.7 Moreover, achieving BP control is among the most cost-effective approaches to improving public health, costing ~$24 000 per quality-adjusted life year gained.8
However, fewer than 50% of US adults with treated hypertension currently meet guideline-recommended goals, and the optimal strategies for achieving intensive BP control in the population are not well defined.9 Single-pill combination (SPC) therapies that combine two or more antihypertensive agents into one pill were designed to address key barriers to effective BP control and have demonstrated efficacy in lowering BP and improving adherence in prior studies.10,11 Several recent large trials additionally highlight their value in a range of resource-constrained settings and their potential to complement multi-intervention strategies in the treatment of hypertension.12-14 Yet, their efficacy as a strategy for achieving intensive BP control and reducing long-term CV risk associated with hypertension is not well described. Therefore, in this study, we aim to evaluate the effects of SPC therapy on intensive BP lowering, target BP control, and downstream risk of CV and adverse events in the SPRINT cohort.
Methods
Data source and study population
We utilized publicly available data from SPRINT, obtained from the National Heart, Lung, and Blood Institute Biologic Specimen and Data Repository Information Coordinating Center. Briefly, SPRINT was a multicentre randomized controlled trial conducted between 2010 and 2015 that compared intensive BP lowering (target SBP < 120 mmHg) with standard treatment (target SBP < 140 mmHg) in adults aged 50 years or older with hypertension and elevated CV risk. The detailed study protocol, eligibility criteria, and primary results have been previously published and are detailed in the Supplemental Methods.1 The choice of BP-lowering therapies was determined by participating providers, guided by treatment algorithms. The use of SPC therapies was encouraged but not required in both treatment arms.1
For the present analysis, we evaluated the use of SPC over the trial period in the cohort of SPRINT participants with complete data on baseline antihypertensive use and at least 1 follow-up medication assessment visit (n = 8623). For primary outcome analysis, we generated a matched cohort of participants with SPC use vs. multi-pill therapy with the same class of antihypertensive medications in the first 6 months of enrolment (1:2 match) using a propensity score methodology described in the Statistical analysis. The final cohort included 2736 matched participants (912 on SPC use and 1824 in the matched control group with multi-pill therapy). All SPRINT participants provided written informed consent at the time of study enrolment. The institutional review boards approved SPRINT at each participating study site. The institutional review board of the University of Texas Southwestern determined that the research was exempt.
Exposure of interest
The primary exposure of interest was SPC antihypertensive therapy compared with a multi-pill therapy approach. Single-pill combination therapy was defined as any antihypertensive medication containing two or more active ingredients in a single formulation. Multi-pill therapy was defined as the use of antihypertensive drug classes delivered as separate formulations. Single-pill combination utilization was assessed at baseline and all scheduled follow-up visits through comprehensive medication review conducted by trained study personnel. Participants were classified based on their combination therapy status at each visit, allowing transitions between SPC and multi-pill therapy over time. Thus, the between-group comparisons of outcomes at each time point reflect the differences among those prescribed SPC vs. multi-pill therapy at each respective time point.
Outcomes
The key outcome of interest was target BP control, defined as SBP < 120 mmHg among participants in the intensive arm and <140 mmHg for participants in the standard treatment arm. We additionally evaluated SBP trajectories on follow-up during two distinct phases: short-term (≤6 months post-randomization) and maintenance (>6 months), reflecting SPRINT’s protocol-specified titration period to achieve target BP within 6 months, followed by maintenance. Clinical outcomes of interest were the risk of SPRINT’s primary composite endpoint (i.e. non-fatal myocardial infarction, stroke, heart failure, or CV death) and serious adverse events (SAEs) as adjudicated and captured by the SPRINT protocol.1
Covariates
Baseline demographic characteristics included age, sex, and self-reported race and ethnicity. Clinical characteristics were characterized at baseline including SBP, serum creatinine and estimated glomerular filtration rate, body mass index, smoking status, and presence of subclinical cardiovascular disease (CVD) (coronary artery calcium score ≥ 400 Agatston units, ankle-brachial index ≤ 0.90, or left ventricular hypertrophy by electrocardiogram, echocardiogram, or cardiac imaging). Medication use was assessed at each study visit and modelled as a time-varying variable where appropriate. Antihypertensive therapies were recorded according to class, including thiazide or thiazide-like diuretics, angiotensin-converting enzyme inhibitors (ACE-Is), angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs), beta-blockers, epithelial sodium channel inhibitors, mineralocorticoid receptor antagonists, loop diuretics, angiotensin Type 1 antagonists, alpha-2 adrenergic agonists, and direct vasodilators.
Statistical analysis
The proportional utilization of different SPC agents was calculated and reported within the full SPRINT cohort as percentages. Rates (per 100 person-months) of SPC use over time in the intensive vs. standard treatment arms were compared using rate ratios derived from Poisson regression models.
To construct the propensity-matched cohort, participants receiving SPC therapy were paired in a 1:2 fashion with controls receiving multi-pill therapies at 6-month follow-up using nearest neighbour matching without replacement based on the following characteristics: treatment arm, age, sex, race, baseline SBP, serum creatinine, body mass index (BMI), antihypertensive medication class, and presence of subclinical CVD. Missing data were observed for serum creatinine and BMI and were imputed to median values. All other variables included in the propensity-scored model were complete and did not require imputation or exclusion. Baseline characteristics of the matched cohort were summarized by baseline SPC vs. multi-pill therapy groups and compared using two-sample t-tests for continuous variables and χ2 tests for categorical variables. Single-pill combination use was modelled as a time-updated variable to account for changes in combination therapy status throughout the study period.
The key outcome of interest was the proportion of participants achieving trial-assigned BP targets in the matched SPC vs. multi-pill therapy groups, reported as percentages at predefined time points. The longitudinal probability of achieving BP control was modelled using generalized linear mixed models for repeated measures (LMMRMs) incorporating fixed effects for SPC use, time, the interaction term time * SPC, and random intercepts for each participant. Predicted log-odds were estimated at 6, 12, 24, and 48 months to derive time-specific odds ratios (ORs) and compare the probability of achieving target BP among participants treated with SPC vs. multi-pill therapies. Time to the first occurrence of target BP was compared between groups using Cox proportional hazards models with SPC use as a time-varying covariate and reported as hazard ratios (HRs) with 95% confidence intervals (CIs). Effect modification by chronic kidney disease (CKD) status was assessed by stratifying participants by baseline estimated glomerular filtration rate (eGFR) (<60 vs. ≥60 mL/min/1.73 m2). The association between SPC use and target BP control at 6 months was examined within each CKD stratum using the same LMMRM approach, and effect modification by CKD status was assessed in a combined model including the SPC * CKD interaction term.
Systolic blood pressure (SBP) trajectories in the matched cohort were modelled using LMMRMs in the short-term and maintenance phases, respectively. The model included time-updated SPC use, fixed effects for time * SPC interaction, and a participant-level random intercept. Estimated marginal means were used to compare SBP at each time point. Systolic blood pressure trajectories were visualized using piecewise linear mixed-effects model splines with a knot at 6 months. Differences in SBP slopes between groups in the short-term BP-lowering phase were tested using likelihood ratio tests to assess differences in the rate of SBP change during treatment initiation and titration. Effect modification by assigned treatment arm was assessed with inclusion of an SPC * time * treatment arm interaction term.
The association between SPC use and the risk of the composite CV outcome and SAEs was examined using Cox models including SPC as a time-dependent variable. To assess the population-level impact of SPC therapies for achieving target BP control, ORs were used to derive absolute risk differences and number needed to treat values. Estimates of impact in the US population are based on values drawn from literature review using a US adult population of 255 million individuals in 2020 and a hypertension prevalence of 32.9%, of whom 51.8% are estimated to have uncontrolled BP.15 All analyses were conducted using R version 4.1.2 with a two-sided P-value of <0.05 indicating significance.
Results
Among 8623 participants included in the full cohort, 803 (9.3%) reported use of an SPC agent at baseline. Participants using SPC on enrolment were more commonly females, were of self-identified Black race, and had lower cardiovascular risk (see Supplementary material online, Table S1). The most prescribed SPC agents at baseline included two-drug combinations of thiazide-like diuretics and ACE-I or ARB (Figure 1A). Following randomization, the rate of SPC use varied by treatment arm, with greater cumulative utilization of SPC agents among participants in the intensive treatment arm. Single-pill combination use initially decreased from pre- to post-randomization in both treatment arms (such that utilization in both arms remained below 8% throughout follow-up) and increased over time in the intensive but not the standard therapy arm [Figure 1B; rate ratio (RR) (95% CI) intensive vs. standard therapy, 1.48 (1.41, 1.56); P < 0.001].
Figure 1.
Utilization of single-pill combination agents in SPRINT. (A) Bar plot demonstrating the proportional utilization of different single-pill combination formulations. Values represent prescribed single-pill combinations over the study period. (B) Proportion of participants receiving single-pill combination therapy over time, stratified by treatment arm. Lines show the percentage of participants prescribed single-pill combinations at each study visit. Shaded areas denote 95% confidence intervals. Single-pill combination use varied significantly by treatment arm, with differences in the rate of use increasing among participants in the intensive treatment arm (systolic blood pressure < 120 mm Hg) and remaining stable in the standard treatment arm (systolic blood pressure < 140 mmHg).
The propensity-matched analysis included 2736 participants (n = 912 in the SPC group and 1824 in the multi-pill therapy group). Baseline characteristics of the matched cohort demonstrated similar demographic, clinical, and medication class profiles between SPC and multi-pill combination users (Table 1). Approximately three-quarters of participants in the matched analysis reported use of a thiazide diuretic at 6 months. A similar proportion reported use of an ACE-I or ARB, and just below half were prescribed a CCB.
Table 1.
Baseline characteristics of the propensity-matched cohort stratified by single-pill combination use at 6 months
| Multi-pill therapy n = 1824 |
SPC therapy n = 912 |
SMD | P-value | |
|---|---|---|---|---|
| Intensive treatment arm (%) | 920 (50.4) | 455 (49.9) | 0.01 | 0.82 |
| Age, mean (SD), y | 68.3 (9.4) | 68.0 (8.9) | 0.03 | 0.41 |
| Female (%) | 786 (43.1) | 373 (40.9) | 0.04 | 0.29 |
| Black race (%) | 669 (36.7) | 343 (37.6) | 0.02 | 0.66 |
| SBP, mean (SD), mmHg | 138.3 (15.3) | 138.2 (16.3) | 0.01 | 0.88 |
| Subclinical CVD (%) | 104 (5.7) | 52 (5.7) | <0.01 | >0.99 |
| Current smoking (%) | 202 (11.1) | 108 (11.8) | 0.02 | 0.59 |
| BMI, mean (SD), kg/m2 | 30.8 (6.1) | 30.6 (5.98) | 0.02 | 0.56 |
| Serum creatinine, mean (SD), μmol/L | 96.4 (31.8) | 95.5 (28.3) | 0.02 | 0.68 |
| eGFR, mean (SD), mL/min/1.73 m2 | 69.98 (20.5) | 70.2 (19.7) | 0.01 | 0.77 |
| Antihypertensive classes | ||||
| Thiazide diuretic (%) | 1370 (75.1) | 686 (75.2) | <0.01 | 0.99 |
| Calcium channel blocker (%) | 880 (48.2) | 434 (47.6) | 0.01 | 0.78 |
| ACE-I (%) | 723 (39.6) | 367 (40.2) | 0.01 | 0.79 |
| ARB (%) | 675 (37.0) | 316 (34.6) | 0.05 | 0.24 |
| Beta-blocker (%) | 720 (39.5) | 363 (39.8) | <0.01 | 0.90 |
| ENaC inhibitor (%) | 277 (15.2) | 190 (20.8) | 0.15 | <0.001 |
| MRA (%) | 106 (5.8) | 49 (5.4) | 0.02 | 0.70 |
| Loop diuretic (%) | 75 (4.1) | 37 (4.1) | <0.01 | >0.99 |
| Angiotensin Type 1 antagonists (%) | 16 (0.9) | 8 (0.9) | <0.01 | >0.99 |
| Alpha-2 adrenergic agonists (%) | 33 (1.8) | 13 (1.4) | 0.03 | 0.56 |
| Direct vasodilator (%) | 55 (3.0) | 28 (3.1) | <0.01 | >0.99 |
Propensity matching was performed in a 2:1 ratio based on criteria met at the 6-month visit. Matching was performed by antihypertensive therapy class, age, sex, race, systolic blood pressure, serum creatinine, subclinical cardiovascular disease, body mass index, and treatment arm.
To convert serum creatinine to mg/dL, divide by 88.4.
SPC, single-pill combination; SMD, standard mean difference; SD, standard deviation; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate; BMI, body mass index (calculated as weight in kilograms divided by height in metres squared); ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ENaC, epithelial sodium channel; MRA, mineralocorticoid receptor antagonist.
Achievement of target blood pressure with single-pill combination vs. multi-pill therapy
The probability of achieving target BP varied significantly by SPC use (Table 2). Among all participants in the matched cohort, 68% of those receiving SPC therapies achieved their treatment-specified target at 6 months, compared with 61% of those with multi-pill therapy use. Among propensity-matched participants, SPC (vs. multi-pill therapy) use was associated with 22% higher odds of achieving target BP control by 6 months [OR (95% CI), 1.22 (1.05, 1.42); P = 0.01; Table 2]. This pattern remained consistent over longer-term follow-up (Figure 2A). A similar pattern of results was observed in treatment arm-stratified analysis with greater odds of achieving target BP with SPC use in both intensive and standard BP control arms (P-interaction time * treatment arm * SPC, 0.936; Table 2; Supplementary material online, Figure S1). In time-to-event analysis, the time to first achievement of target BP control was significantly shorter with SPC (vs. multi-pill therapy) use [HR (95% CI), 1.50 (1.36, 1.65); P < 0.001]. In subgroup analysis, the association between SPC use and target BP control at 6 months did not vary by CKD status (P-interaction SPC * CKD = 0.27; Supplementary material online, Table S2).
Table 2.
Probability of achieving treatment-specified systolic blood pressure target over time
| Time (months) |
Participants on SPC |
Participants on multi-pill |
SPC achieving target |
Multi-pill achieving target |
Odds ratio (95% CI) | P-value |
|---|---|---|---|---|---|---|
| Overall cohort | ||||||
| 6 | 296 (11.1) | 2364 (88.9) | 201 (67.9) | 1435 (60.7) | 1.22 (1.05, 1.42) | 0.011 |
| 12 | 254 (9.9) | 2318 (90.1) | 158 (62.2) | 1377 (59.4) | 1.23 (1.06, 1.42) | 0.005 |
| 24 | 257 (10.4) | 2205 (89.6) | 161 (62.6) | 1303 (59.1) | 1.17 (1.03, 1.34) | 0.016 |
| 48 | 82 (9.5) | 781 (90.5) | 52 (63.4) | 429 (54.9) | 1.27 (1.0, 1.63) | 0.05 |
| Intensive treatment arm | ||||||
| 6 | 168 (12.4) | 1192 (87.6) | 101 (60.1) | 643 (53.9) | 1.34 (1.09, 1.65) | 0.006 |
| 12 | 153 (11.4) | 1184 (88.6) | 91 (59.5) | 674 (56.9) | 1.25 (1.03, 1.51) | 0.023 |
| 24 | 158 (12.2) | 1138 (87.8) | 93 (58.9) | 661 (58.1) | 1.11 (0.93, 1.32) | 0.25 |
| 48 | 60 (12.8) | 407 (87.2) | 38 (63.3) | 217 (53.3) | 1.19 (0.88, 1.60) | 0.26 |
| Standard treatment arm | ||||||
| 6 | 128 (9.8) | 1172 (90.2) | 100 (78.1) | 792 (67.6) | 1.22 (0.97, 1.54) | 0.09 |
| 12 | 101 (8.2) | 1134 (91.8) | 67 (66.3) | 703 (62.0) | 1.21 (0.97, 1.50) | 0.09 |
| 24 | 99 (8.5) | 1067 (91.2) | 68 (68.7) | 642 (60.2) | 1.17 (0.96, 1.43) | 0.12 |
| 48 | 22 (5.6) | 374 (94.4) | 14 (63.6) | 212 (56.7) | 1.50 (0.96, 2.34) | 0.08 |
Values shown represent n (%) or odds ratio (95% confidence interval).
Changes over time in utilization of single-pill combination or multi-pill therapy represent treatment switching and study attrition.
Probability estimates in achievement of target blood pressure are derived from generalized logistic mixed-effects models with single-pill combination use modelled as a time-varying exposure and accounting for participant-level random effects and adjusted for interaction of time * single-pill combination use.
Predicted log-odds were calculated at prespecified time points to generate time-specific odds ratios.
SPC, single-pill combination; SBP, systolic blood pressure; CI, confidence interval.
Figure 2.
Association of single-pill combination vs. the multi-pill therapy with blood pressure control in the propensity-matched cohort. (A) Odds of achieving target systolic blood pressure control over time in the matched single-pill combination vs. the multi-pill therapy group. The odds are derived from generalized logistic mixed-effects models with shaded areas representing 95% confidence intervals. (B) Estimated mean systolic blood pressure trajectories among participants in the propensity-matched cohort. Target systolic blood pressure control is defined as systolic blood pressure < 120 mmHg for participants in the intensive treatment arm and systolic blood pressure < 140 mmHg for those in the standard treatment arm. The spline plots with a knot at 6 months visualize trajectories of systolic blood pressure in the acute blood pressure-lowering (≤6 months) and chronic maintenance (>6 months) phases. Systolic blood pressure trajectories are modelled using linear mixed-effects models with repeated measures, including a random intercept for each participant and fixed effects for single-pill combination use, time (in months), and interaction term for time × single-pill combination.
Systolic blood pressure trajectories over time in single-pill combination vs. multi-pill therapy groups
In the short-term BP-lowering phase (≤6 months), the achieved SBP varied significantly between SPC and multi-pill therapy groups [Table 3; SBP difference at 6 months (95% CI), −1.9 mmHg (−2.8, −0.96)]. The rate of SBP decline in the first 6 months was significantly greater among participants with SPC use compared with multi-pill therapy [−2.0 mmHg/month (95% CI, −2.3, −1.7) vs. −1.2 mmHg/month (95% CI, −1.3, −1.06); P < 0.001; Table 4], with a similar pattern observed across both treatment arms (Figure 2B). In the chronic maintenance phase of the trial (>6-month follow-up), SPC (vs. multi-pill therapy) use was associated with sustained lower achieved SBP by ~2 mmHg until termination of the trial, with no significant effect modification by treatment arm (see Supplementary material online, Figure S2).
Table 3.
Estimated marginal means of systolic blood pressure in the short-term blood pressure-lowering (≤6 months) and maintenance (>6 months) phases by single-pill combination use in the propensity-matched cohort
| Time (months) |
SPC therapy, SBP in mmHg (95% CI) |
Multi-pill therapy, SBP in mmHg (95% CI) |
Estimated difference (95% CI) |
P-difference |
|---|---|---|---|---|
| Overall | ||||
| 0 | 136.8 (135.9, 137.8) | 136.5 (135.9, 137.1) | 0.30 (−0.71, 1.31) | 0.56 |
| 3 | 126.7 (125.7, 127.7) | 128.1 (127.7, 128.6) | −1.48 (−2.49, −0.47) | 0.004 |
| 6 | 125.5 (124.6, 126.4) | 127.3 (126.9, 127.8) | −1.86 (−2.76, −0.96) | <0.001 |
| 12 | 125.9 (125.0, 126.7) | 127.9 (127.6, 128.4) | −2.06 (−2.90, −1.21) | <0.001 |
| 24 | 125.9 (125.0, 126.7) | 128.0 (127.6, 128.4) | −2.18 (−2.97, −1.39) | <0.001 |
| 48 | 125.8 (124.4, 127.1) | 128.5 (127.9, 129.0) | −2.69 (−4.10, −1.28) | <0.001 |
| Intensive SBP control treatment arm | ||||
| 0 | 137.0 (135.8, 138.2) | 136.0 (135.2, 136.7) | 1.03 (−0.33, 2.38) | 0.14 |
| 3 | 121.8 (120.6, 123.1) | 122.4 (121.8, 122.9) | −0.54 (−1.80, 0.73) | 0.41 |
| 6 | 119.5 (118.4, 120.6) | 120.6 (120.1, 121.1) | −1.06 (−2.18, 0.06) | 0.06 |
| 12 | 119.2 (118.2, 120.2) | 120.7 (120.2, 121.1) | −1.45 (−2.47, −0.43) | 0.005 |
| 24 | 118.8 (117.9, 119.7) | 120.1 (119.7, 120.6) | −1.31 (−2.25, −0.37) | 0.006 |
| 48 | 119.9 (118.3, 121.4) | 121.1 (120.4, 121.7) | −1.23 (−2.84, 0.38) | 0.14 |
| Standard SBP control treatment arm | ||||
| 0 | 137.2 (136.0, 138.5) | 137.0 (136.2, 137.8) | 0.23 (−1.22, 1.67) | 0.76 |
| 3 | 131.8 (130.3, 133.2) | 134.0 (133.4, 134.5) | −2.17 (−3.67, −0.68) | 0.004 |
| 6 | 132.3 (131.0, 133.6) | 134.3 (133.8, 134.7) | −1.95 (−3.27, −0.64) | 0.004 |
| 12 | 134.4 (133.2, 135.7) | 135.5 (135.1, 135.9) | −1.08 (−2.36, 0.21) | 0.10 |
| 24 | 135.4 (134.3, 136.6) | 136.0 (135.9, 136.7) | −0.85 (−2.05, 0.36) | 0.17 |
| 48 | 133.3 (130.8, 135.7) | 136.1 (135.5, 136.8) | −2.88 (−5.41, −0.36) | 0.025 |
Estimated marginal means (95% confidence interval) derived from linear mixed-effects model with single-pill combination use treated as a time-varying exposure, random intercept for each participant and fixed effects for single-pill combination status, time (in months), and interaction term for time * single-pill combination. SPC, single-pill combination; SBP, systolic blood pressure; CI, confidence interval.
Table 4.
Monthly change in systolic blood pressure in the short-term blood pressure-lowering (≤6 months) and maintenance (>6 months) phase by single-pill combination use
| Time (months) | SPC therapy, ΔSBP in mmHg (95% CI) |
Multi-pill therapy, ΔSBP in mmHg (95% CI) |
P-difference | |
|---|---|---|---|---|
| Primary analysis | ||||
| Short-term BP lowering | Overall cohort | −2.0 (−2.3, −1.7) | −1.2 (−1.3, −1.1) | <0.001 |
| (≤6 months) | Standard treatment | −1.0 (−1.4, −0.5) | −0.2 (−0.4, −0.07) | 0.002 |
| Intensive treatment | −2.8 (−3.2, −2.4) | −2.1 (−2.3, −1.9) | 0.001 | |
| Maintenance phase (>6 months) | Overall cohort | −0.01 (−0.05, 0.03) | 0.01 (0.0, 0.02) | 0.30 |
| Standard treatment | −0.03 (−0.1, 0.03) | 0.01 (0, 0.03) | 0.16 | |
| Intensive treatment | 0.01 (−0.04, 0.05) | 0 (−0.01, 0.02) | 0.94 |
Change in systolic blood pressure derived from linear mixed-effects model with single-pill combination use treated as a time-varying exposure, random intercept for each participant and fixed effects for single-pill combination status, time (in months), and interaction term for time * single-pill combination. No interaction by treatment arm was observed in the primary or propensity-matched cohorts (P-interaction = 0.683 in the propensity cohort).
SPC, single-pill combination; SBP, systolic blood pressure; CI, confidence interval.
Clinical outcomes among participants with single-pill combination vs. multi-pill therapy use
Although the rate of the primary composite endpoint was numerically lower among participants in the SPC (vs. multi-pill therapy) group (5.4% vs. 6%), we observed no significant difference in the risk between the two groups in time-to-event analysis [Table 5; SPC vs. multi-pill therapy (ref.) HR (95% CI), 0.7 (0.39, 1.26); P = 0.23]. Time to first SAE [HR (95% CI), 0.93 (0.72, 1.19); P = 0.56] and cumulative SAEs [RR (95% CI), 0.99 (0.8, 1.22); P = 0.90] were similar between SPC and multi-pill therapy groups. Additionally, the incidence of specific SAEs of interest, including hypotension, syncope, electrolyte disturbances, acute kidney injury, and bradycardia, was similar between treatment groups during the first 6 months of follow-up (see Supplementary material online, Table S3).
Table 5.
Association of single-pill combination use with the risk of major adverse cardiovascular events
| Multi-pill therapy n = 1824 |
SPC therapy n = 912 |
HR (95% CI) | P-value | |
|---|---|---|---|---|
| Major adverse cardiovascular events | ||||
| Primary composite outcome (%) | 109 (6.0) | 49 (5.4) | 0.70 (0.39, 1.26) | 0.23 |
| HF or CV death (%) | 86 (4.7) | 35 (3.8) | 0.62 (0.3, 1.27) | 0.19 |
| ASCVD (%) | 70 (3.8) | 24 (2.6) | 0.79 (0.38, 1.64) | 0.53 |
Time-dependent Cox proportional hazards models with single-pill combination use as a time-varying covariate were used. The reference group was participants utilizing multi-pill therapies. Analysis conducted in propensity-matched cohort. Primary composite outcome includes non-fatal myocardial infarction, stroke, heart failure, or cardiovascular death. Atherosclerotic cardiovascular disease includes non-fatal myocardial infarction, stroke, or cardiovascular death.
SPC, single-pill combination; HR, hazard ratio; CI, confidence interval; CV, cardiovascular; ASCVD, atherosclerotic cardiovascular disease; HF, heart failure.
Projected population-level impact of single-pill combination vs. multi-pill therapy implementation in the USA
We estimated the projected impact of SPC use for achieving target BP control using contemporary US data on rates of hypertension prevalence and control. Given an observed ~20% higher odds of achieving target SBP control with use of SPC therapies, the estimated absolute risk difference between SPC and multi-pill therapy use was 4.3%, indicating that for every 1000 individuals treated with SPCs (vs. equivalent multi-pill therapy), 43 would achieve target BP control. Given an estimated US population size of 255 million adults, a 32.9% prevalence of hypertension, and a 51.8% BP control rate under current treatment paradigms, our findings suggest that widespread utilization of SPC therapies would result in an additional 1.9 million US adults achieving target BP control.
Discussion
In this post hoc analysis of SPRINT, participants treated with SPC therapies were more likely to achieve BP control and reached BP targets more rapidly than those receiving multi-pill therapies. In matched analysis, SPC (vs. multi-pill therapy) use was associated with a more rapid and robust decline in SBP within the first 6 months of therapy and lower sustained SBP over long-term follow-up. Despite greater BP reductions, we observed no increase in the risk of SAEs among participants receiving SPCs. Moreover, based on their clinical efficacy in SPRINT, we estimate that widespread uptake of SPCs in the USA could result in an additional 1.9 million adults achieving target BP control. Taken together, our findings suggest that SPCs present a safe and effective opportunity for improving intensive BP control and can contribute to progress towards population-level BP control goals in the USA (Graphical Abstract).
Prior studies, including SPRINT, have demonstrated that relatively modest improvements in SBP towards optimal levels can lead to substantial reductions in CV risk, particularly among individuals at elevated baseline risk.1,16 Although consensus is lacking on the ideal timeframe for achieving BP goals, clinical trial data suggest that early BP control may both improve the likelihood of sustained control and reduce the risk of clinical CV events among high-risk hypertensive patients.17 Accordingly, rapid BP control within 3 months was endorsed in the 2024 European Society of Cardiology guidelines for the management of hypertension.3 Yet under current treatment paradigms, fewer than 50% of adults achieve BP control in the USA at all, and between 30 and 50% are estimated to achieve their goals within 18 months of treatment initiation.15,18
In this study, SPC therapy was associated with a 22% higher likelihood of achieving target BP control by 6 months, with 68% of participants on SPC therapy achieving target BP control in that timeframe. Furthermore, the time to first achievement of target BP control was up to 50% faster with SPC (vs. multi-pill therapy) use. These findings align with existing trial data on the use of SPCs as initial therapy, where 70% of participants achieved BP control within 3–6 months and 78% reached this goal by 6 months with additional titration.13,20-22 A meta-analysis of SPC trials additionally showed that among nine studies comparing SPCs with free equivalent therapy, five showed superior BP control with SPCs and only one favoured multi-pill therapy.11 Moreover, in two of the nine studies, ≥49% of participants not achieving optimal BP goals on multi-pill therapy subsequently met goal when switched to SPC agents.11 Notably, in SPRINT, SPC use was associated with lower SBP despite protocol-driven medication titration among all patients and even after accounting for differences in antihypertensive class in matched analysis, suggesting that the benefits of the SPC approach described in our study are more likely related to advantages of the SPC strategy rather than constituent agent or provider behaviour.
Several mechanistic and practical advantages underlie the efficacy of SPC therapies in achieving robust BP reduction, including synergistic physiologic effects between component therapies, reduced therapeutic inertia, and increased adherence and tolerability.22 In recent years, SPC therapies have received renewed attention as part of a strategy for achieving intensive BP control and, in 2017, were for the first time recommended as the preferred initial therapy in the treatment of Stage 2 hypertension in American College of Cardiology/American Heart Association guidelines.23 Recent trials have sought to expand the applications of SPCs to new contexts and utilize novel triple-agent formulations, thereby expanding the body of evidence regarding their efficacy.12,13,24 However, data capturing utilization of SPC agents in nationally representative samples demonstrate declines in SPC usage over the same period, with fewer than one in three adults with hypertension currently reporting use of an SPC agent.25,26 The causes of this implementation gap are multifactorial, involving barriers at the patient, provider, and health system level. Among providers, commonly cited concerns with SPCs include lack of flexibility for titration (due to limited choices of agents and doses in existing formulations), hesitations regarding use in higher-risk patients and those with comorbidities, and fear of increased side effect burden.10 In SPRINT, we observe reflections of this trend, with low overall utilization of SPC therapies in the sample and preference for thiazide-based combination agents that are largely representative of SPC utilization and market availability in the USA.27,28 Yet, our findings directly address concerns about the SPC strategy, highlighting both the superior efficacy of commonly used SPC agents in achieving BP lowering and their similar side effect profile to free agents among individuals with increased CV risk. Although a Cochrane review of SPC trials suggests SPCs may, in aggregate, be associated with increased adverse effects (32% vs. 27%), prior cost-effectiveness analyses note that such increases would be offset by the benefits of improved BP control over long-term follow-up.29,30
Few prior trials of SPC therapies have directly examined the impact of SPC use on CV outcomes and mortality.29 Published in 2023, the START study leveraged retrospective claims data in Germany with a propensity-matched design to compare four SPC formulations with their identical multi-pills, finding a 24–48% reduction in all-cause mortality associated with SPC use and concomitant reductions in composite CV events.31 Additional observational data from Hungary support these findings, suggesting that SPC agents may be associated with a ~30% reduction in major adverse cardiovascular events compared with multi-pill therapy.32 In our post hoc analysis from the SPRINT trial using a subset of participants, we did not observe a significant association of SPC (vs. multi-pill therapy) use and risk of adverse CV outcomes, likely owing to low event rates and lack of statistical power. Future studies with larger sample size of longer-term follow-up are needed to determine whether the BP differences observed between SPC and multi-pill therapy groups may have long-term implications for CV risk.
Our study findings have important clinical implications. In the decade since SPRINT, BP control rates in the USA have declined, and the optimal strategies for translating SPRINT’s findings to practice have not been well defined or implemented.9 Hypertension remains the most prevalent risk factor for CVD in the USA with rates anticipated to increase in the next 25 years. Achieving population-wide BP control is critical to improving CV public health, and our findings reinforce the safety and efficacy of SPCs for improving progress towards that goal. We report that for every 24 patients treated with SPCs, one will achieve target BP control. This amounts to ~1.9 million additional patients achieving BP control if SPCs were successfully implemented today. However, closing the implementation gap in SPC uptake will require multi-level engagement to expand availability of SPC therapies, educate providers regarding evidence-based strategies for BP control, and address patient concerns.10,27,28 Large-scale randomized trials are urgently needed to identify the most effective implementation strategies and interventions to ensure progress towards population-level BP control.
Our study has several limitations. First, we present findings from a non-prespecified post hoc analysis subject to residual confounding between groups. Second, because SPC use was uncommon in the SPRINT cohort, the propensity-matched analysis presents results from a relatively small subset of participants limiting the generalizability of our findings to the broader hypertensive population. Although this approach reduced confounding by measured covariates, including antihypertensive therapy class, it introduced the possibility of selection bias as unmeasured patient and provider characteristics influencing the decision to prescribe SPC therapy may not have been fully captured. Third, while participants were matched on antihypertensive therapy class, differences in treatment dose intensity and titration strategies cannot be excluded and may contribute to BP differences observed between groups. In particular, limited options for dose adjustments in patients receiving SPC therapy may have amplified treatment effects by enabling more consistent dose escalation, reflecting a potential strategic benefit of SPC therapy in real-world settings. Moreover, data on adherence, which in prior studies have driven some of the differences observed between SPC and multi-pill regimens, were not available for analysis, limiting our ability to identify the factors contributing to the superiority of SPC therapy. Finally, low event rates resulted in inadequate power to detect differences in CV outcomes by SPC use; therefore, our findings should be considered hypothesis generating.
Conclusions
Single-pill combination therapy resulted in more rapid and sustained BP reduction and a greater likelihood of achieving BP control compared with multi-pill therapy approach. Future research is needed to identify optimal strategies for implementing SPC-based approaches at the population level to translate the public health benefits of intensive BP control.
Supplementary Material
Supplementary material is available at European Journal of Preventive Cardiology.
Key findings.
Patients taking single-pill combinations were 22% more likely to reach their target blood pressure within 6 months compared with those taking separate pills, and their blood pressure dropped more quickly during the first 6 months of treatment (−2.0 vs. −1.2 mmHg per month).
Single-pill combination users maintained lower blood pressure throughout the entire study period (up to 4 years) and experienced similar risk of serious side effects as patients taking separate pills, indicating these combination medications are both more effective and equally safe.
Funding
S.R. is supported by an NIH K12 Career Development Award (5K12TR004529).
Conflict of interest:
M.W.S. reports honoraria from Idorsia Pharmaceuticals and non-financial support from Merck, is on the advisory board of descendantsDNA, and is the founder of ReCODE Medical. N.K. has received consultant fees from Heart Test Laboratories, Tricog Health, Idorsia Pharmaceuticals, and Science37. M.D.H has received travel support from the World Heart Federation and consulting fees from PwC Switzerland. M.D.H has pending patents for heart failure polypills. M.D.H has an appointment at The George Institute for Global Health, which has a patent, license, and has received investment funding with intent to commercialize fixed-dose combination therapy through its social enterprise business, George Medicines. W.V. has received consultant fees from AstraZeneca and research support from the National Institute on Aging (R01AG076660, R33/R61AG068486). A.P. has received grant funding outside the present study from Applied Therapeutics and Gilead Sciences; has received honoraria outside the present study as an advisor/consultant for Tricog Health Inc., Lilly USA, Rivus, Cytokinetics, Roche Diagnostics, Axon Therapies, Medtronic, Edwards Lifesciences, Science37, Novo Nordisk, Bayer, Merck, Sarfez Pharmaceuticals, and Emmi Solutions; and has received non-financial support from Pfizer and Merck. A.P. is also a consultant for Palomarin Inc. with stock compensation. He has received research support from the National Institute on Aging GEMSSTAR Grant (1R03AG067960-01) and the National Institute on Minority Health and Disparities (R01MD017529).
Data availability
The data used in this study were obtained from the Systolic Blood Pressure Intervention Trial through the National Heart, Lung, and Blood Institute Biologic Specimen and Data Repository Information Coordinating Center. Data are available to researchers upon submission of a data use agreement with the Biologic Specimen and Data Repository Information Coordinating Center.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data used in this study were obtained from the Systolic Blood Pressure Intervention Trial through the National Heart, Lung, and Blood Institute Biologic Specimen and Data Repository Information Coordinating Center. Data are available to researchers upon submission of a data use agreement with the Biologic Specimen and Data Repository Information Coordinating Center.