Chapter 13: When to start medication and what target to use

Should treatment depend on total cardiovascular risk?

A recent meta-analysis found that blood-pressure lowering was beneficial across almost the entire starting-pressure range. Relative-risk reduction was similar across cardiovascular-risk strata, while absolute benefit was greater at higher risk. This has been interpreted as an argument for treating according to cardiovascular risk and targeting people at highest risk regardless of pressure.

Current guidance does not support risk replacing blood-pressure thresholds. High-risk and very-high-risk people have a larger absolute benefit, but also a disproportionate residual risk that treatment cannot fully reverse. Conversely, withholding treatment from low-risk younger people ignores the possible prevention or delay of silent HMOD and later high, less reversible risk. Cardiovascular risk should always be assessed, but the decision to start medication should also follow confirmed clinic pressure.

Clinic threshold for starting medication

All major recommendations support medication plus lifestyle measures for grade 2 or grade 3 hypertension and for grade 1 hypertension with high cardiovascular risk. Medication in grade 1 with low or moderate risk, without cardiovascular disease, diabetes, CKD or HMOD, was historically controversial because many trials recruited people with at least grade 2 disease and older age.

More recent meta-analyses nevertheless found fewer cardiovascular events and deaths in grade 1 hypertension. In the analysis most relevant to genuinely low-risk grade 1 hypertension, a 7 mmHg systolic reduction in four trials involving 8,073 people reduced the combined risk of stroke and coronary disease by 31%. HOPE-3 also found a 27% cardiovascular-risk reduction after a 6 mmHg systolic reduction in a mostly untreated, intermediate-risk subgroup with baseline systolic pressure above 143.5 mmHg, mean 154 mmHg.

Therefore, lifestyle advice should generally be accompanied by antihypertensive medication in grade 1 hypertension regardless of risk. In borderline grade 1, low-risk people without HMOD, a lifestyle-only trial for about three to six months may be considered if adherence and the chance of control are realistic. If control is not achieved within a few months, medication is necessary.

Pressure below 140/90 mmHg

Earlier guidance advised against medication in low-risk people with high-normal pressure. Reasons included the fact that many trial participants were already taking medication, HOPE-3 did not show benefit in low- or intermediate-risk people with high-normal systolic pressure, and a meta-analysis of 13 trials or subgroups involving 22,128 low- to moderate-risk untreated participants found no cardiovascular benefit.

Current guidance still recommends not starting medication solely for high-normal pressure in low- to moderate-risk people; lifestyle intervention is appropriate because it reduces progression to hypertension. A large individual-participant meta-analysis suggested that a 5 mmHg systolic reduction could reduce risk even from starting values below 120 mmHg, but interpretation is difficult because many participants had been treated previously and subgroup results were inconsistent. Stopping treatment in the comparison group may also have artificially increased risk.

The decision may differ in very-high-risk people with high-normal pressure and established cardiovascular disease. Meta-analysis of ten trials or randomised subgroups involving 26,863 people with cardiovascular disease found that a small systolic reduction lowered stroke risk, and another analysis in coronary disease with mean baseline systolic pressure 138 mmHg found about 10% fewer major cardiovascular events, without a clear survival benefit. Many such people are already receiving guideline-directed therapy, such as RAS blockers or beta-blockers, for their direct cardiovascular indications.

Starting medication in older adults

Recommendations use different age thresholds, commonly 60–65 years and sometimes 80 years. Evidence that medication benefits people above 60–65 is strong. The historical treatment threshold of 160 mmHg in older adults reflected the entry criteria of early trials, not proof that lower values should be ignored.

HYVET supports treatment in people around 80 years old, including isolated systolic hypertension. A lower treatment threshold, such as 150 mmHg, may also be considered because benefits occurred below 150/80 mmHg and a later SPRINT analysis in adults aged 75–84 found benefit from starting pressures well below 160 mmHg. Treatment that is well tolerated should generally continue after a person reaches 80 because stopping long-term medication can be followed by rebound complications.

The exception is a very old person with systolic pressure 120 mmHg or lower, severe orthostatic hypotension, polypharmacy or marked frailty. Gradual deprescribing may be considered cautiously, but evidence for benefit is lacking. HYVET participants had a median age near 83, so randomised evidence in people approaching 90 or older remains limited. Frail, multimorbid people and those with recurrent admissions need individual assessment; dedicated trials in this population are still needed.

Clinic blood-pressure targets

Earlier ESC/ESH guidance recommended first reducing pressure below 140/90 mmHg in all patients and, if tolerated, aiming for 130/80 mmHg or lower, while avoiding below 120/70 mmHg because evidence of additional benefit was uncertain and adverse effects could cause treatment discontinuation. In a large northern Italian population, stopping treatment for several months was associated with approximately 40% more hospitalisation for coronary disease, stroke or heart failure than continuing treatment.

STEP was the main newer target trial. A Cochrane analysis of 11 randomised trials involving 38,688 people compared below 135/85 mmHg with the usual below 140/90 mmHg target. Achieved pressure was about 122.8/82.0 versus 135.0/85.0 mmHg. The authors estimated that 167–250 people would need treatment to the lower target for one person to benefit, while 37 would need treatment for one person to be harmed. Interpretation is limited because the lower target was arbitrary, SPRINT used unattended measurements in some participants and the achieved systolic value was closer to below 120 than below 135.

A second Cochrane analysis in people with prior cardiovascular disease also found no clear clinical advantage, but included fewer trials, had a high risk of performance bias and low-certainty evidence. In contrast, an individual-participant meta-analysis associated a 5 mmHg systolic reduction with lower outcomes across starting pressures above 170 to below 120 mmHg, although those below 120 were under 2% of the database and included SPRINT.

Large trial meta-analyses suggest that compared with treated systolic pressure above 140 mmHg, cardiovascular events and all-cause mortality fall at 130–139 mmHg and may fall further at 120–129 mmHg. Diastolic values below 80 mmHg were associated with progressively fewer events than 80–89 or 90 mmHg, including in people aged 65 or older. However, treatment discontinuation and kidney adverse effects increase as targets become lower.

For most patients, a treated systolic target below 140 mmHg and diastolic below 80 mmHg is therefore reasonable. A range of 120–129 mmHg systolic can be pursued when well tolerated, but the evidence for extra benefit is uncertain and treatment should not be continued at the expense of symptoms, organ hypoperfusion or adverse effects.

Ambulatory versus clinic targets

A major evidence gap is that no large randomised trial has used home or ambulatory blood pressure to guide treatment. A small older trial found no conclusive difference in cardiovascular events between ambulatory- and office-guided care, while another study suggested that 24-hour reduction improved left-ventricular hypertrophy more than office reduction and home reduction had an intermediate effect.

Home and ambulatory pressure are more predictive than clinic pressure, but it remains unknown whether treatment guided by them protects more than clinic-guided treatment or what their optimal targets should be. Targets are inferred indirectly from 24-hour averages corresponding to a clinic target below 130/80 mmHg, with important limitations. The clinic–out-of-office gap generally narrows during treatment; in some studies, clinic and 24-hour systolic pressure converged around 120 mmHg.

Speed and time in range

Trials traditionally define achieved pressure as an average over treatment. VALUE and other analyses show that earlier control, within six months or even one month, is associated with fewer events than delayed control in high-risk patients. The greater the proportion of visits with controlled pressure, the lower the risk, independent of the average pressure over the whole treatment period. Similar findings have been reported after RDN and in type 2 diabetes.

These findings support avoiding a long titration period with uncontrolled pressure, particularly in high-risk people, and support starting with two drugs when appropriate. Clinicians should assess sustained control across visits rather than dismissing a single high value as incidental. Future trials should analyse duration and time in the therapeutic range.

Residual risk

Effective treatment markedly reduces hypertension-related events but does not restore cardiovascular risk to that of age-, sex- and ethnicity-matched people without hypertension. This excess is called residual risk and can persist for approximately 20 years.

Residual risk may reflect genetic susceptibility, delayed treatment with partly irreversible structural and functional cardiovascular change, poor control of other risk factors, long-term blood-pressure variability and incomplete control of real-world or nocturnal pressure despite a good clinic value. In treated hypertension, time spent controlled predicts outcome independently of the average treatment pressure. Visit-to-visit variability, as shown in analyses such as ONTARGET-TRANSCEND, adds risk beyond the average value. Broad use of home monitoring may help assess consistency.

Why target evidence is difficult

Optimal targets differ between guidelines and over time because evidence is inconsistent and not equally strong in every phenotype. People with left-ventricular hypertrophy illustrate this uncertainty: some real-world data associate systolic pressure below 130 or 120 mmHg with fewer events, whereas LIFE and VALUE analyses reported higher mortality in selected patients with ECG-LVH at lower treated pressure. Increased myocardial oxygen demand and microvascular disease may make perfusion more vulnerable.

Post-hoc observational analyses sometimes show a J-shaped relationship between pressure and outcomes. They cannot determine whether low-pressure risk reflects hypoperfusion, frailty or a high-risk illness. Patients therefore do not respond uniformly to one target. Future studies should identify safer targets for distinct clinical subgroups and clarify the mechanisms of this heterogeneity.

Studies mentioned

• HOPE-3 showed benefit in a selected intermediate-risk group with elevated baseline pressure.
• SPRINT compared below 120 with below 140 mmHg in higher-risk adults without diabetes; its measurement method and exclusions matter.
• HYVET supports treatment in very old adults, while frailty and orthostatic symptoms must guide individual decisions.
• Individual-participant meta-analyses support proportional risk reduction but do not eliminate clinical heterogeneity.