{
  "abstract": "Objective To directly compare the efficacy and safety of different intensive systolic blood pressure targets (<120 or <130 mm Hg) versus usual care on cardiovascular and renal outcomes.Design Meta-analysis of randomised controlled trials.Data sources Web of Science and Medline, from inception to 20 May 2025.Eligibility criteria for selecting studies Randomised controlled trials comparing intensive versus usual systolic blood pressure targets. Studies reported cardiovascular disease or kidney outcomes, or both.Results The study included 18 randomised controlled trials of 60 629 participants. Intensive control of systolic blood pressure significantly reduced the risk of major adverse cardiovascular events (relative risk 0.82, 95% confidence interval (CI) 0.78 to 0.87, P<0.001), including myocardial infarction, stroke, heart failure, and death from cardiovascular disease. Systolic blood pressure targets of <120 mm Hg and <130 mm Hg provided comparable cardiovascular protection. Intensive control of systolic blood pressure increased the risk of the composite chronic kidney disease outcome (relative risk 1.40, 95% CI 1.01 to 1.94, P=0.046), but with a likely higher risk for the target of <120 mm Hg. A systolic blood pressure target of <120 mm Hg also reduced the risk of albuminuria, but increased the risk of bradycardia and hypotension.Conclusions Intensive control of systolic blood pressure provided substantial cardiovascular benefits but increased the risk of renal adverse events. A systolic blood pressure target of <130 mm Hg had a similar degree of cardiovascular protection as <120 mm Hg with a more favourable renal safety profile, supporting a personalised risk based approach to treatment intensification.Trial registration PROSPERO CRD42025629962.",
  "authors": [
    {
      "affiliations": [
        "Division of Nephrology, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory of Multi-Organ Injury Prevention and Treatment, Guangdong Provincial Institute of Nephrology, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, China"
      ],
      "name": "Yuanyuan Zhang"
    },
    {
      "affiliations": [
        "Division of Nephrology, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory of Multi-Organ Injury Prevention and Treatment, Guangdong Provincial Institute of Nephrology, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, China"
      ],
      "name": "Yanjun Zhang"
    },
    {
      "affiliations": [
        "Division of Nephrology, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory of Multi-Organ Injury Prevention and Treatment, Guangdong Provincial Institute of Nephrology, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, China"
      ],
      "name": "Sisi Yang"
    },
    {
      "affiliations": [
        "Division of Nephrology, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory of Multi-Organ Injury Prevention and Treatment, Guangdong Provincial Institute of Nephrology, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, China"
      ],
      "name": "Xiaoqin Gan"
    },
    {
      "affiliations": [
        "Division of Nephrology, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory of Multi-Organ Injury Prevention and Treatment, Guangdong Provincial Institute of Nephrology, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, China"
      ],
      "name": "Yu Huang"
    },
    {
      "affiliations": [
        "Division of Nephrology, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory of Multi-Organ Injury Prevention and Treatment, Guangdong Provincial Institute of Nephrology, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, China"
      ],
      "name": "Yiwei Zhang"
    },
    {
      "affiliations": [
        "Division of Nephrology, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory of Multi-Organ Injury Prevention and Treatment, Guangdong Provincial Institute of Nephrology, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, China"
      ],
      "name": "Yiting Wu"
    },
    {
      "affiliations": [
        "Division of Nephrology, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory of Multi-Organ Injury Prevention and Treatment, Guangdong Provincial Institute of Nephrology, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, China"
      ],
      "name": "Fan Fan Hou"
    },
    {
      "affiliations": [
        "Division of Nephrology, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory of Multi-Organ Injury Prevention and Treatment, Guangdong Provincial Institute of Nephrology, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, China"
      ],
      "name": "Xianhui Qin"
    }
  ],
  "full_text": "WHAT IS ALREADY KNOWN ON THIS TOPIC The benefits of lowering blood pressure to reduce the risk of cardiovascular disease are well establishedResults from recent trials comparing intensive versus usual targets for reducing systolic blood pressure have been conflicting, particularly for renal outcomes and optimal targets in high risk populations, leading to inconsistent guideline recommendationsWHAT THIS STUDY ADDS This large meta-analysis directly compared two of the most common intensive systolic blood pressure targets (<120  v <130 mm Hg)Although both targets had comparable cardiovascular protection, safety profiles were differentThe systolic blood pressure target of <120 mm Hg had a significantly higher risk of renal impairment and hypotension, whereas the target of <130 mm Hg represented a safer compromise for most patientsHOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE, OR POLICY The findings argue against a universal one-size-fits-all intensive target and provide an evidence base for individualised treatmentThe results can inform more nuanced clinical guidelines for clinicians to adapt targets for systolic blood pressure based on the individual's cardiovascular risk, baseline kidney function, and tolerance for treatmentFuture research should focus on specific antihypertensive drug regimens and under-represented groups, such as elderly peopleIntroduction Raised blood pressure is a key modifiable risk factor for major adverse cardiovascular events, chronic kidney disease, and premature mortality worldwide. 1 Although the benefits of lowering blood pressure are well established, the optimal treatment target for systolic blood pressure is uncertain, particularly in high risk populations, such as those with previous stroke, chronic kidney disease, or diabetes.2–6 Results from recent randomised trials comparing intensive (<130 or <120 mm Hg) versus usual (<130-150 mm Hg) targets for reducing systolic blood pressure have been conflicting in terms of lowering the risk of major adverse cardiovascular events and chronic kidney disease,7–9 contributing to inconsistent recommendations in major clinical guidelines.10–12Recognising that these treatment strategies are implemented by drug treatment interventions is important. Therefore, comparing systolic blood pressure targets mainly involves evaluating different intensities of antihypertensive drug treatments. To resolve the ongoing controversy, we conducted a systematic review and meta-analysis of randomised controlled trials to directly compare the efficacy and safety of different intensive systolic blood pressure control strategies (<120 or <130 mm Hg) against conventional management (<140 mm Hg). Our comprehensive evaluation assessed a range of outcomes, including major adverse cardiovascular events, progression of chronic kidney disease, incidence of cancer, and safety events, with prespecified subgroup analyses based on trial characteristics (eg, diabetes specific and stroke specific trials) and baseline renal function (chronic kidney disease status). Our analysis provides a rigorous, direct comparison of the risk-benefit profile associated with different intensive systolic blood pressure targets, achieved through intensification of drug treatments, across key clinical domains.Materials and methods This meta-analysis adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines 13 and was prospectively registered in PROSPERO.Data sources, searches, and study selection We systematically searched Web of Science and Medline with medical subject headings terms and keywords related to cardiovascular and kidney outcomes, and targets for reducing systolic blood pressure. Search terms included (cardiovascular disease OR coronary heart disease OR stroke OR heart failure OR mortality OR chronic kidney disease) AND (systolic blood pressure target <120 OR systolic blood pressure goal <120 OR systolic blood pressure target <130 OR systolic blood pressure goal <130 OR systolic blood pressure target 110-130 OR systolic blood pressure goal 110-130 mm Hg). We included randomised controlled trials in any language. Databases were searched from inception to 20 May 2025, supplemented by manual searches of bibliographies and expert consultation.In eligible trials, participants were randomised to intensive (<130 mm Hg or lower) versus usual (<150 mm Hg or lower) systolic blood pressure targets, and the studies reported cardiovascular disease or kidney outcomes, or both. Studies focusing only on diastolic blood pressure or mean arterial pressure were excluded. Two reviewers (Yuanyuan Zhang and Yanjun Zhang) independently screened the studies, with disagreements resolved by consensus or with a third reviewer (Xianhui Qin) to minimise bias.Data extraction and quality assessment Two investigators independently extracted the study characteristics (trial name, publication year, and country or region), participant characteristics (age, sex, and comorbidities), intervention details (systolic blood pressure targets and length of follow-up), and outcomes (sample size, event rates, and baseline or achieved systolic blood pressure). Discrepancies were resolved through team consensus.Outcome definitions The primary outcomes were incident major adverse cardiovascular events and composite chronic kidney disease outcomes. Major adverse cardiovascular events included stroke, myocardial infarction, heart failure, and death from cardiovascular disease. When unavailable, we used the trial's primary composite cardiovascular outcome or the most similar alternative. The composite chronic kidney disease outcome comprised end stage kidney disease, estimated glomerular filtration rate <15 mL/min/1.73 m 2, or >50% reduction in estimated glomerular filtration rate from baseline in patients with chronic kidney disease (baseline estimated glomerular filtration rate <60 mL/min/1.73 m²). For participants with no chronic kidney disease, the chronic kidney disease outcome included estimated glomerular filtration rate <60 mL/min/1.73 m² with >30% reduction in estimated glomerular filtration rate from baseline. If unavailable, the most comparable chronic kidney disease outcome was used. Secondary outcomes included incident albuminuria, heart failure, stroke, myocardial infarction, death from cardiovascular causes, cancer, pneumonia, arrhythmias, and all cause mortality. Online supplemental table 1 has detailed definitions of the study outcomes.SP110.1136/bmjmed-2025-001791.supp1Supplementary dataRisk of bias assessment The quality of the studies was independently assessed with the revised Cochrane Collaboration risk-of-bias tool 14 for the domains randomisation process, deviations from intended interventions, missing outcome data, measurement of the outcome, selection of the reported result, and overall bias. Discrepancies were resolved by team consensus.Data synthesis and analysis Main analysis We compared intensive versus usual systolic blood pressure targets on primary outcomes (major adverse cardiovascular events and composite chronic kidney disease) and secondary outcomes (including albuminuria, cardiovascular events, mortality, and safety outcomes). Analyses were grouped by the population characteristics of the trials (ie, diabetes specific (exclusively including participants with diabetes), stroke specific (exclusively including participants with a history of stroke), and other trials) and systolic blood pressure intensive targets (<120 v <130 mm Hg) to evaluate differential effects across populations and treatment targets.Subgroup analyses We examined major adverse cardiovascular events outcomes for key subgroups in all trials, including age (<65  v ≥65 years), sex (men v women), previous diabetes (yes v no), previous cardiovascular disease (yes v no), previous stroke (yes v no), and baseline chronic kidney disease status (estimated glomerular filtration rate <60 mL/min/1.73 m², yes v no). For diabetes specific trials, participants were also grouped by baseline concentrations of glycated haemoglobin A1c (HbA1c ≤8.0 v >8.0%) and duration of diabetes (<10 v ≥10 years). Outcome analyses for chronic kidney disease were grouped by baseline chronic kidney disease status (yes v no).Statistical methods The effects of intensive versus usual treatment targets for systolic blood pressure are expressed as relative risks with 95% confidence intervals (CIs). Primary analyses were performed with random effects models, with common effect models applied to evaluate the consistency and robustness of the findings, particularly to assess the potential influence of smaller trials. Heterogeneity between studies was assessed with Cochran's Q test and quantified with the inconsistency index (I²) to evaluate inconsistency, with τ² values reported to estimate the variance of true effects. A P value <0.10 for Cochran's Q test and I² ≥50% were considered indicative of significant heterogeneity. Sensitivity analyses were conducted by sequentially excluding each trial to assess robustness. Publication bias was assessed with Begg's funnel plot and Egger's test. An asymmetric funnel plot with a P value <0.05 was considered suggestive of potential publication bias. All statistical analyses were conducted with R software (version 4.3.2) and the R package meta.Patient and public involvement This study was a meta-analysis of previously published literature, thus engaging patients or the public in its design, conduct, reporting, or dissemination would not have been appropriate or feasible. Following publication, we plan to share the results via academic and public research platforms to ensure broad dissemination.Results Online supplemental figure 1 summarises the study selection procedure. We identified 906 articles from the database searches. After screening the titles and abstracts, 842 articles were excluded, and full text evaluation was performed on 64 articles. After a thorough review, 18 articles with 60 629 participants met the inclusion criteria and were included in the meta-analysis.7–9 15–29Study characteristics and quality assessment The analysis included 18 trials with diverse populations (mean age 36.5-80.5 years; 23.0-80.7% women). Four trials focused exclusively on participants with diabetes (diabetes specific trials) and six trials included only participants with a history of stroke (stroke specific trials). Baseline systolic blood pressure ranged from 123.4 to 163.3 mm Hg, with mean achieved systolic blood pressure differences of 1.9-15.7 mm Hg. Intensive targets were systolic blood pressure <120 mm Hg (11 trials) or <130 mm Hg (seven trials), with length of follow-up 0.5-7.0 years ( online supplemental table 2).Online supplemental table 3 details the drug treatment strategies for reducing systolic blood pressure in the intensive and usual treatment groups. Although the core drug treatment algorithm was consistent between the two groups, the lower systolic blood pressure target in the intensive group required the use of a greater number of antihypertensive drug treatments on average.Quality assessment showed a low risk of bias in 17 trials, with one study (Hypertension Objective Treatment Based on Measurement by Electrical Devices of Blood Pressure, HOMED-BP) showing some concerns because of low initial treatment adherence (online supplemental table 4). Begg's funnel plot analysis and Egger's test indicated no significant publication bias (online supplemental figure 2).Primary outcomes Major adverse cardiovascular events outcomes Compared with usual systolic blood pressure targets, intensive control of systolic blood pressure consistently reduced the risk of major adverse cardiovascular events across all trial populations (random effects model: relative risk 0.82, 95% CI 0.78 to 0.87, P<0.001; common effect model: relative risk 0.82, 0.77 to 0.87, P<0.001), with significant effects in diabetes specific (random effects model: relative risk 0.82, 0.74 to 0.91, P<0.05; common effect model: relative risk 0.82, 0.74 to 0.91, P<0.05) and stroke specific populations (random effects model: relative risk 0.82, 0.69 to 0.96, P<0.05; common effect model: relative risk 0.80, 0.68 to 0.94, P<0.05) ( figure 1). Analyses by treatment intensity showed that the systolic blood pressure target of <120 mm Hg (random effects model: relative risk 0.84, 95% CI 0.79 to 0.89, P<0.05; common effect model: relative risk 0.84, 0.78 to 0.89, P<0.05) and the target of <130 mm Hg (random effects model: relative risk 0.69, 0.52 to 0.91, P<0.05; common effect model: relative risk 0.76, 0.66 to 0.86, P<0.05) significantly reduced the risk of major adverse cardiovascular events compared with usual control (figure 2). The test for subgroup differences between the two intensive targets was not significant for all trial populations (figure 1) or stroke specific populations (online supplemental figure 3; P for interaction >0.05 for both). All diabetes trials exclusively used the systolic blood pressure target of <120 mm Hg (figure 1 and table 1).Figure 1Forest plot of intensive versus usual systolic blood pressure targets on the risk of major adverse cardiovascular events, grouped by characteristics of the trial population: diabetes specific trials7 16 18 26 (exclusively including participants with diabetes), stroke specific trials21 24 25 27–29 (exclusively including participants with a history of stroke), and other trials.8 9 17 19 20 22 23 CI=confidence interval; SBP=systolic blood pressureFigure 2Forest plot of intensive versus usual systolic blood pressure targets on the risk of major adverse cardiovascular events. Comparison of systolic blood pressure intensive targets <120 mm Hg7 8 16 18 19 22 23 26 27 29 versus <130 mm Hg.9 17 20 21 24 25 28 CI=confidence interval; SBP=systolic blood pressureTable 1Risk of major adverse cardiovascular events: intensive versus usual systolic blood pressure treatment targets across subgroupsSubgroupNo of trialsIntensive v usual systolic blood pressure targets*Relative risk (95% CI)I²P for interactionAll included trials     All trials170.82 (0.78 to 0.87)0.33 Age (years):     <657 8 18 2640.83 (0.74 to 0.94)0.000.74  ≥657–9 18 2350.81 (0.73 to 0.90)0.00 Sex:     Men7–9 18 23 2660.82 (0.75 to 0.89)0.000.58  Women7–9 18 23 2660.85 (0.76 to 0.94)0.00 Previous cardiovascular disease:     No7 8 18 23 2650.82 (0.75 to 0.90)0.000.26  Yes7 8 18 19 23 2660.89 (0.81 to 0.98)0.00 Previous chronic kidney disease:     No7 8 18 2340.83 (0.76 to 0.90)0.210.91   Yes7 8 18 2340.84 (0.71 to 0.99)0.00 Previous stroke:     No810.87 (0.76 to 1.00)—0.72   Yes8 21 24 25 27–2970.85 (0.75 to 0.96)0.38 Previous diabetes:     No8 9 17 2340.78 (0.70 to 0.87)0.400.26  Yes7–9 16 18 2660.84 (0.78 to 0.91)0.00Diabetes specific trials     All trials40.82 (0.74 to 0.91)0.00 Age (years):     <657 18 2630.81 (0.71 to 0.94)0.000.80  ≥657 1820.84 (0.72 to 0.97)0.00 Sex:     Men7 18 2630.82 (0.72 to 0.92)0.000.71   Women7 18 2630.85 (0.73 to 0.99)0.00 Previous cardiovascular disease:     No7 18 2630.78 (0.69 to 0.89)0.000.46   Yes7 18 2630.85 (0.71 to 1.02)0.00 Previous chronic kidney disease:     No7 1820.82 (0.73 to 0.92)0.000.89  Yes7 1820.80 (0.59 to 1.09)0.00 Duration of diabetes (years):     <107 18 2630.82 (0.69 to 0.97)0.340.78   ≥107 18 2630.85 (0.74 to 0.96)0.00 Baseline HbA1c (%):     <8.07 1820.74 (0.64 to 0.87)0.000.06   ≥8.07 18 2630.91 (0.79 to 1.04)0.00*Random effects model.CI, confidence interval; HbA1c, glycated haemoglobin A1c.We found consistent treatment effects of intensive control of systolic blood pressure for all prespecified subgroups (age, sex, previous cardiovascular disease, and baseline chronic kidney disease status) in both the overall and diabetes specific trial populations (all P for interaction >0.05). In the diabetes specific trial populations, we saw a marginally significant interaction (P for interaction=0.06) for baseline glycaemic control, with a significant benefit in patients with HbA1c ≤8.0% (random effects model: relative risk 0.74, 95% CI 0.64 to 0.87, P<0.05) (table 1).Composite chronic kidney disease outcomes Intensive control of systolic blood pressure was associated with a significantly increased risk of composite chronic kidney disease outcomes than usual targets (random effects model: relative risk 1.40, 95% CI 1.01 to 1.94, P=0.046; common effect model: relative risk 1.47, 1.35 to 1.59, P<0.001) ( figure 3). Tests for subgroup differences indicated a potential risk gradient, with higher point estimates for the target of <120 mm Hg than for the <130 mm Hg target. This finding was further supported by the common effect model (P for interaction=0.001), which suggested robustness against the potential influence of small studies (figure 4).Figure 3Forest plot of intensive versus usual systolic blood pressure targets on risk of composite chronic kidney disease, grouped by characteristics of the trial population: diabetes specific trials7 15 18 26 (exclusively including participants with diabetes), stroke specific trials21 29 (exclusively including participants with a history of stroke), and other trials.8 9 23 CI=confidence interval; SBP=systolic blood pressureFigure 4Forest plot of intensive versus usual systolic blood pressure targets on risk of composite chronic kidney disease. Comparison of systolic blood pressure intensive targets <120 mm Hg7 8 15 18 23 26 29 versus <130 mm Hg.9 21 CI=confidence interval; SBP=systolic blood pressureThe increased risk of composite chronic kidney disease outcomes was consistent, irrespective of baseline kidney function (online supplemental figure 4), and robust across various definitions of chronic kidney disease outcomes. The composite severe kidney endpoint (end stage kidney disease, an estimated glomerular filtration rate <15 mL/min/1.73 m², or ≥50% reduction in estimated glomerular filtration rate) showed a consistent association, as did outcomes based only on reduction in estimated glomerular filtration rate (online supplemental figures 5A and 5B). Based on five studies, intensive lowering of blood pressure did not significantly affect the risk of incident end stage kidney disease (online supplemental figure 5C).Secondary outcomes Differential effects of blood pressure targets Cardiovascular disease outcomes Intensive control of systolic blood pressure significantly reduced the risks of myocardial infarction (random effects model: relative risk 0.84, 95% CI 0.74 to 0.94, P=0.003), stroke (random effects model: relative risk 0.80, 0.73 to 0.87, P<0.001), and heart failure (random effects model: relative risk 0.75, 0.62 to 0.90, P=0.002). The tests for subgroup differences between the targets <120 mm Hg and <130 mm Hg were not significant for any of these outcomes (all P for interaction >0.05) ( table 2 and online supplemental figures 6-8).Table 2Comparison of secondary outcomes for different systolic blood pressure targets: intensive (<120 and <130 mm Hg) versus usual targetSecondary outcomesNo of trialsIntensive v usual systolic blood pressure targets*Relative risk (95% CI)I²P for interactionMyocardial infarction:    All trials7–9 16–21 23–26 28 29150.84 (0.74 to 0.94)0.000.26 Systolic blood pressure target <120 mm Hg7 8 16 18 19 23 26 2980.86 (0.76 to 0.99)0.00 Systolic blood pressure target<130 mm Hg9 17 20 21 24 25 2870.73 (0.57 to 0.95)0.00Stroke:     All trials7–9 16–21 23–29160.80 (0.73 to 0.87)0.140.93  Systolic blood pressure target <120 mm Hg7 8 16 18 19 23 26 27 2990.80 (0.73 to 0.88)0.32 Systolic blood pressure target <130 mm Hg9 17 20 21 24 25 2870.79 (0.66 to 0.95)0.00Heart failure:    All trials7–9 17–19 23 26 28 29100.75 (0.62 to 0.90)0.140.06 Systolic blood pressure target <120 mm Hg7 8 18 19 23 26 2970.78 (0.64 to 0.94)0.08 Systolic blood pressure target <130 mm Hg9 17 2830.32 (0.13 to 0.78)0.00Cardiovascular disease mortality:    All trials7–9 16 18 20 21 23–25 28110.74 (0.62 to 0.90)0.000.62  Systolic blood pressure target <120 mm Hg7 8 16 18 2350.73 (0.56 to 0.94)0.39 Systolic blood pressure target <130 mm Hg9 20 21 24 25 2860.81 (0.58 to 1.14)0.00All cause mortality:    All trials7–9 15–26 28 29170.91 (0.82 to 1.01)0.000.18  Systolic blood pressure target <120 mm Hg78 15 16 18 19 22 23 26 29100.88 (0.77 to 0.99)0.00 Systolic blood pressure target <130 mm Hg9 17 20 21 24 25 2871.02 (0.85 to 1.23)0.00Albuminuria:     All trials (systolic blood pressure target <120 mm Hg)7 18 23 26 0.84 (0.77 to 0.90)0.03—Cancer:    All trials7 8 15 18 19 22 23 25–27 29110.88 (0.79 to 1.00)0.000.92  Systolic blood pressure target <120 mm Hg78 15 18 19 22 23 26 27 29100.88 (0.79 to 1.00)0.00 Systolic blood pressure target <130 mm Hg2511.02 (0.07 to 15.84)—Hypotension:    All trials7–9 16–19 21 2392.24 (1.36 to 3.68)0.420.03 Systolic blood pressure target <120 mm Hg7 8 16 18 19 2363.26 (1.52 to 6.98)0.44 Systolic blood pressure target <130 mm Hg9 17 2131.32 (1.04 to 1.68)0.00Syncope:    All trials7–9 18 19 21 23 28 2991.52 (1.25 to 1.86)0.000.56  Systolic blood pressure target <120 mm Hg7 8 18 19 23 2961.50 (1.22 to 1.84)0.00 Systolic blood pressure target <130 mm Hg9 21 2831.88 (0.90 to 3.94)0.00Electrolyte abnormality:    All trials7 8 16–18 22 23 2681.22 (1.05 to 1.42)0.000.69  Systolic blood pressure target <120 mm Hg7 8 16 18 22 23 2671.22 (1.04 to 1.41)0.00 Systolic blood pressure target <130 mm Hg1711.98 (0.18 to 21.80)—Bradycardia:    All trials18 23 2831.70 (0.81 to 3.54)0.490.11  Systolic blood pressure target <120 mm Hg18 2322.13 (1.08 to 4.23)0.31 Systolic blood pressure target <130 mm Hg2810.67 (0.20 to 2.31)—Tachyarrhythmia:     All trials (systolic blood pressure target <120 mm Hg)8 16 2330.90 (0.69 to 1.17)0.23—Pneumonia:     All trials (systolic blood pressure target <120 mm Hg)7 8 23 2941.03 (0.90 to 1.18)0.48—*Random effects model.CI, confidence interval.Mortality and cancer outcomes Intensive control of systolic blood pressure significantly reduced death from cardiovascular disease (random effects model: relative risk 0.74, 95% CI 0.62 to 0.90, P=0.002). A reduction in all cause mortality (random effects model: relative risk 0.91, 0.82 to 1.01, P=0.079) and cancer (random effects model: relative risk 0.88, 0.79 to 1.00, P=0.041) with intensive control of systolic blood pressure was not convincingly shown. Tests for subgroup differences between the two intensive targets were not significant ( table 2, figures 5 and 6, and online supplemental figures 9 and 10).Figure 5Forest plot of intensive versus usual systolic blood pressure targets on risk of cancer, grouped by characteristics of the trial population: diabetes specific trials7 15 18 26 (exclusively including participants with diabetes), stroke specific trials25 27 29 (exclusively including participants with a history of stroke), and other trials.8 19 22 23 CI=confidence interval; SBP=systolic blood pressureFigure 6Forest plot of intensive versus usual systolic blood pressure targets on risk of cancer. Comparison of systolic blood pressure intensive targets <120 mm Hg7 8 15 18 19 22 23 26 27 29 versus <130 mm Hg.25 CI=confidence interval; SBP=systolic blood pressureRenal and safety outcomes Intensive control of systolic blood pressure to a target of <120 mm Hg was associated with a reduction in the risk of albuminuria (random effects model: relative risk 0.84, 95% CI 0.77 to 0.90, P<0.001). This effect could not be evaluated for the target <130 mm Hg ( table 2 and online supplemental figure 11).Intensive control of systolic blood pressure was associated with a significant increase in the risk of hypotension (random effects model: relative risk 2.24, 95% CI 1.36 to 3.68, P=0.001), syncope (random effects model: relative risk 1.52, 1.25 to 1.86, P<0.001), and electrolyte abnormalities (random effects model: relative risk 1.22, 1.05 to 1.42, P=0.009). Tests for subgroup differences between the targets <120 mm Hg and <130 mm Hg showed no significant heterogeneity in the risk of syncope or electrolyte abnormalities (P for interaction >0.05 for both). Subgroup analysis for hypotension, however, indicated a potential risk gradient, with higher point estimates for the <120 mm Hg target than the <130 mm Hg target (P for interaction=0.014) (table 2 and online supplemental figures 12-14).Although intensive control of systolic blood pressure did not significantly affect the overall risk of bradycardia, a significantly increased risk was specifically seen in the intensive group targeting <120 mm Hg (random effects model: relative risk 2.13, 95% CI 1.08 to 4.23, P<0.05) (table 2 and online supplemental figure 15). Intensive control of systolic blood pressure had no significant effect on the risk of tachyarrhythmia or pneumonia compared with the usual care group (table 2 and online supplemental figures 16 and 17).Effects in high risk populations Among high risk populations, intensive control of systolic blood pressure had different benefits. In diabetes specific trials (all targeting <120 mm Hg), we found a 37% reduction in the risk of stroke (relative risk 0.63, 95% CI 0.44 to 0.90, P<0.05) ( online supplemental figure 18) and 17% lower risk of albuminuria (relative risk 0.83, 0.75 to 0.92, P<0.05) (online supplemental figure 11), whereas in stroke specific trials (n=6 randomised controlled trials, including four studies targeting <130 mm Hg), we saw a significant 20% reduction in the risk of recurrent stroke (relative risk 0.80, 0.66 to 0.97, P<0.05) (online supplemental figure 18). We found no significant effects for other secondary outcomes in these populations (online supplemental figures 19-22).Sensitivity analyses Sensitivity analyses confirmed the robustness of our primary findings. The sequential exclusion approach showed consistent risk reductions for both major adverse cardiovascular events and composite chronic kidney disease outcomes for all study exclusions ( online supplemental figure 23). When we excluded INFINITY (Intensive Versus Standard Ambulatory Blood Pressure Lowering to Prevent Functional Decline in the Elderly) Trial, which specifically enrolled elderly patients (≥75 years) with white matter hyperintensity lesions, the treatment effect in stroke specific trials remained largely unchanged (random effects model: relative risk 0.84, 95% CI 0.71 to 1.00; online supplemental figure 24), suggesting that the overall findings were not driven by this unique patient subgroup.Discussion Principal findings In this meta-analysis of 18 randomised controlled trials, we have provided a detailed comparison of intensive versus usual control of systolic blood pressure. Our findings indicated that intensive control of systolic blood pressure (targeting <120 or <130 mm Hg) significantly reduced the risk of major adverse cardiovascular events, including myocardial infarction, stroke, and heart failure, compared with usual targets. This cardiovascular benefit, however, was offset by an increased risk of composite chronic kidney disease outcomes. A critical finding of our analysis was the difference in risk-benefit profile between the two intensive targets: although both targets (<120 and <130 mm Hg) provided a similar reduction in the risk of major adverse cardiovascular events, the target of <120 mm Hg was associated with a higher risk of renal impairment and specific adverse events, such as hypotension.Cardiovascular outcomes Our findings showed that intensive control of systolic blood pressure provided significant cardiovascular protection, reducing major adverse cardiovascular events, including myocardial infarction, stroke, heart failure, and cardiovascular mortality. This benefit was consistent across the subgroup analyses, strengthening the evidence for intensive management in high risk populations, such as those with previous stroke or diabetes. Our results align with a recent meta-analysis by Bergmann et al, 30 which included five trials (39 434 participants) and also showed reductions in mortality and major adverse cardiovascular events. Our analysis extended this evidence by directly comparing the two most common intensive targets. We showed that both targets (<120 and <130 mm Hg) were effective in reducing the risk of cardiovascular disease, indicating that the benefits of intensive control can be achieved without trying to reach the lowest possible target in all patients. This key finding provides clinicians with valuable flexibility in setting individualised treatment goals.Renal outcomes: a delicate balance Renal outcomes had a complex risk-benefit profile. On the one hand, intensive control of systolic blood pressure targeting <120 mm Hg significantly reduced the risk of albuminuria, a marker of early kidney damage. On the other hand, intensive control was associated with a 40% increased risk of the composite chronic kidney disease outcome (reduction in estimated glomerular filtration rate and end stage kidney disease), with evidence suggesting a steeper risk gradient for the systolic blood pressure target of <120 mm Hg than the target of <130 mm Hg. This finding highlights a critical trade-off in clinical management: intensive control may prevent microvascular kidney injury (reflected by albuminuria) but could simultaneously increase the risk of macrovascular or haemodynamic renal impairment in susceptible individuals, possibly because of the greater drug treatment burden or profound blood pressure lowering itself. This dichotomy requires careful monitoring of renal function when trying to achieve intensive systolic blood pressure targets.The observed disparity in the association between intensive control of systolic blood pressure and the composite severe kidney endpoint (which included ≥50% reduction in estimated glomerular filtration rate or progression to <15 mL/min/1.73 m², or end stage kidney disease) but not incident end stage kidney disease only, is a recognised phenomenon in nephrology trials, as reflected in previous consensus reports.31 This disparity can likely be attributed to the relatively short duration of many of the included trials and the consequently low number of definite end stage kidney disease events, which limits the statistical power to detect a significant effect on this ultimate outcome. In contrast, the composite endpoint of a sustained ≥50% reduction in estimated glomerular filtration rate, a well validated surrogate marker strongly predictive of future end stage kidney disease, provides a more sensitive measure of progressive loss of kidney function within the typical timeframe of a trial. Therefore, the significant association between intensive control of systolic blood pressure and this clinically meaningful composite outcome underscores a genuine, although earlier stage, risk of accelerated progression of chronic kidney disease with intensive lowering of systolic blood pressure, which may not yet have translated into a detectable increase in the number of patients with end stage kidney disease.Cancer and other safety outcomes We found a borderline significant reduction in the risk of cancer associated with the systolic blood pressure target of <120 mm Hg. This finding, however, should be interpreted with caution. Cancer was a secondary outcome in our analysis, and a recent large scale individual participant data meta-analysis by Nazarzadeh et al, 32 which examined blood pressure lowering and risk of cancer as a primary outcome, found no significant association. The difference in findings may reflect methodological variations, because Nazarzadeh et al examined reduction in blood pressure as a continuous variable rather than specific intensive targets. Both studies, however, conclude that intensive control of blood pressure does not increase the risk of cancer, which should reassure clinicians about the oncological safety of this strategy.In terms of safety, intensive control of systolic blood pressure, particularly targeting <120 mm Hg, significantly increased the risks of hypotension, syncope, electrolyte abnormalities, and bradycardia. These findings highlight the need for vigilant monitoring and personalised regimen titration to reduce the risks associated with strict blood pressure targets.Study implications for clinical practice and policy The findings of this analysis advocate for a nuanced application of intensive control of systolic blood pressure, beyond a universal target. Given the comparable cardiovascular benefits of both targets (<120 and <130 mm Hg), but a more favourable renal safety profile for the target of <130 mm Hg, we propose a stratified approach: for most patients, particularly those with or at risk of chronic kidney disease, a target of <130 mm Hg represents a sensible strategy, optimising cardiovascular benefit while minimising the risk of renal and other adverse events. A target of <120 mm Hg could be used for two specific scenarios: patients with a very high risk of cardiovascular disease but a low risk of renal disease, and in those patients where reducing albuminuria is a primary goal. This approach requires caution, together with vigilant monitoring for adverse effects. This risk based framework will allow clinicians to adapt the intensity of treatment and can inform more personalised guideline recommendations.Strengths and limitations of this study The study had several strengths, including analysis of 18 trials with >60 000 participants, a direct comparison of specific systolic blood pressure targets, and a comprehensive assessment of efficacy and safety outcomes across key clinical domains. Several limitations, however, warrant consideration. Firstly, the included trials predominantly enrolled participants with a high risk of cardiovascular disease, and therefore our findings might not be applicable to individuals with uncomplicated hypertension. Secondly, our study did not examine the potential different effects of specific antihypertensive drug classes (eg, angiotensin converting enzyme inhibitors-angiotensin II receptor blockers, calcium channel blockers, or diuretics) on renal or cancer outcomes. As a study level meta-analysis, we lacked individual patient drug treatment data to analyse the effects of antihypertensive drug classes. Future individual participant data meta-analyses are needed to answer this important question. Thirdly, although intensive control of systolic blood pressure showed benefits across age groups, our findings are limited by the under-representation of patients aged ≥75 years; only INFINITY specifically enrolled elderly patients. This evidence gap needs to be considered, given that older adults represent the fastest growing hypertensive population. Finally, the observed associations, particularly for secondary outcomes, should be interpreted as generating hypotheses rather than providing conclusive evidence, highlighting areas for future research. Future studies should validate these findings in broader populations, particularly in older adults and in patients with a low risk of hypertension.Conclusions Our systematic review and meta-analysis suggested that intensive control of systolic blood pressure provided significant cardiovascular benefits but also increased the risk of renal adverse events. The key clinical insight is that a systolic blood pressure target of <130 mm Hg seems to offer similar cardiovascular protection as a target of <120 mm Hg, but with a potentially more favourable renal safety profile. These findings support an individualised approach to managing blood pressure, where the intensity of treatment is adapted to the patient's specific cardiovascular risk, renal function, and tolerance for treatment.SP210.1136/bmjmed-2025-001791.supp2Supplementary data",
  "title": "Outcome specific optimal systolic blood pressure targets in high risk patients, balancing cardiovascular benefits, renal risks, and cancer prevention: meta-analysis of randomised controlled trials",
  "uid": "1780c6f1-b864-58b6-ad4c-a4a2ed35fd62"
}