Hypertension in 2026: Landmark Trials and the 2025 Guideline Every Clinician Should Know

Hypertension remains one of the most important modifiable cardiovascular risk factors encountered in clinical practice.

For hospitalists and primary care clinicians, managing high blood pressure can seem routine—until it isn’t.

How aggressively should blood pressure be lowered?

What target should clinicians use?

How should cardiovascular risk influence treatment?

Should older adults receive intensive treatment?

What is the preferred approach to resistant hypertension?

Can thiazide-like diuretics still work in advanced chronic kidney disease?

And what should clinicians make of emerging therapies such as aldosterone synthase inhibitors and RNA interference?

Several landmark trials have changed how clinicians answer these questions.

The 2025 U.S. high blood pressure guideline brought much of this evidence together into an updated framework for clinical practice.

Here are the studies—and the practical lessons—clinicians should know.

The 2025 Hypertension Guideline: What Changed?

Before reviewing individual trials, it helps to understand where current U.S. recommendations stand.

The 2025 multisociety high blood pressure guideline replaced the 2017 ACC/AHA guideline and incorporates newer evidence regarding cardiovascular risk, treatment thresholds, home monitoring, combination therapy, and resistant hypertension.

One of the central recommendations is an overarching blood pressure treatment goal of:

<130/80 mm Hg for most adults

The guideline also emphasizes that treatment should be individualized in certain populations.

Another important change is the use of the PREVENT cardiovascular risk equations when deciding whether some patients with stage 1 hypertension should receive pharmacologic therapy.

For clinicians, the larger message is that blood pressure management is increasingly risk-based rather than number-based alone.

That framework has been built on years of clinical trial evidence.

1. SPRINT: The Trial That Changed Blood Pressure Targets

The Systolic Blood Pressure Intervention Trial, better known as SPRINT, remains one of the most influential hypertension trials of the modern era.

SPRINT enrolled more than 9,000 adults at increased cardiovascular risk with systolic blood pressure of at least 130 mm Hg.

Importantly, patients with diabetes or a history of stroke were excluded.

Participants were randomized to two strategies:

Intensive treatment: systolic blood pressure target <120 mm Hg

Standard treatment: systolic blood pressure target <140 mm Hg

The trial was stopped early after intensive treatment demonstrated a significant reduction in the primary composite cardiovascular outcome.

All-cause mortality was also lower with intensive treatment.

But there was an important tradeoff.

Some adverse events—including hypotension, electrolyte abnormalities, and acute kidney injury or failure—occurred more frequently with intensive treatment.

Clinical Takeaway

SPRINT demonstrated that appropriately selected patients at increased cardiovascular risk can benefit from more intensive blood pressure reduction.

But it did not prove that every adult should be treated to a systolic blood pressure below 120 mm Hg.

Patient selection matters.

Measurement technique matters.

Comorbidities matter.

And clinicians must balance potential cardiovascular benefit against adverse effects.

2. STEP: Intensive Blood Pressure Treatment in Older Adults

A common concern with intensive hypertension treatment is whether lower blood pressure targets are appropriate for older adults.

The STEP trial helped address that question.

The trial studied adults aged 60 to 80 years with hypertension and compared an intensive systolic blood pressure target of approximately 110–130 mm Hg with a standard target of approximately 130–150 mm Hg.

Intensive treatment reduced the incidence of major cardiovascular events.

Clinical Takeaway

Chronologic age alone should not automatically exclude a patient from more intensive blood pressure management.

But that doesn’t mean every older adult should receive the same target.

Frailty, orthostatic symptoms, falls, comorbid disease, polypharmacy, life expectancy, and treatment tolerance all matter.

The better question is not:

“Is this patient too old for intensive treatment?”

It is:

“What blood pressure strategy provides the best balance of benefit and risk for this particular patient?”

3. SSaSS: Can Changing Salt Reduce Cardiovascular Events?

Not every important hypertension trial involves another medication.

The Salt Substitute and Stroke Study (SSaSS) evaluated a potassium-enriched salt substitute compared with regular salt.

The study demonstrated reductions in stroke and major cardiovascular events in the population studied.

The concept is attractive because it addresses blood pressure through a relatively simple dietary intervention.

But there is an important clinical caveat.

Increasing potassium intake is not appropriate for every patient.

Patients with impaired potassium excretion, significant kidney disease, hyperkalemia, or medications affecting potassium balance may require particular caution.

Clinical Takeaway

Lifestyle intervention remains a foundational part of hypertension management.

But even seemingly simple dietary recommendations should be individualized.

“Eat more potassium” is not a universally safe prescription.

4. CLICK: Chlorthalidone in Advanced Chronic Kidney Disease

Hypertension in patients with advanced chronic kidney disease can be particularly difficult to manage.

Historically, clinicians often assumed that thiazide and thiazide-like diuretics become largely ineffective as kidney function declines.

The CLICK trial challenged that assumption.

Patients with stage 4 chronic kidney disease and poorly controlled hypertension were randomized to chlorthalidone or placebo.

Chlorthalidone produced meaningful reductions in blood pressure.

Why CLICK Matters to Hospitalists

Hospitalists frequently encounter patients with:

• Chronic kidney disease
• Resistant hypertension
• Volume abnormalities
• Electrolyte disorders
• Acute kidney injury superimposed on CKD
• Complex antihypertensive regimens

CLICK expanded the therapeutic conversation surrounding hypertension in advanced CKD.

But chlorthalidone is not risk-free.

Electrolytes, kidney function, volume status, and adverse effects require monitoring.

Clinical Takeaway

Advanced CKD does not automatically eliminate thiazide-like diuretics as a therapeutic option.

Patient selection and monitoring remain essential.

5. PATHWAY-2: Why Spironolactone Became Central to Resistant Hypertension

Before calling hypertension “resistant,” clinicians should make sure it actually is.

Apparent treatment resistance may result from:

• Inaccurate blood pressure measurement
• White-coat effect
• Medication nonadherence
• Inadequate medication dosing
• Suboptimal drug combinations
• Excess dietary sodium
• Medications that increase blood pressure
• Secondary hypertension

Once true resistant hypertension has been established, PATHWAY-2 remains a pivotal trial.

The study compared several potential add-on therapies in patients with resistant hypertension.

Spironolactone was the most effective of the tested fourth-line agents for lowering blood pressure.

Clinical Takeaway

For many patients with true resistant hypertension, spironolactone remains an important add-on therapy when appropriate.

But clinicians need to consider:

• Potassium
• Kidney function
• Drug interactions
• Adverse effects
• Contraindications

The broader lesson from PATHWAY-2 is also important:

Resistant hypertension deserves a systematic evaluation—not simply an endless sequence of additional medications.

6. BaxHTN: Aldosterone Synthase Inhibition Enters Phase 3

One of the most important recent hypertension trials involves baxdrostat, an aldosterone synthase inhibitor.

Aldosterone is an appealing therapeutic target in difficult-to-control hypertension, particularly because inappropriate aldosterone activity may contribute to sodium retention and elevated blood pressure.

The phase 3 BaxHTN trial evaluated baxdrostat in patients with uncontrolled or resistant hypertension despite background antihypertensive therapy.

At 12 weeks, both studied doses of baxdrostat produced significantly greater reductions in seated systolic blood pressure than placebo.

That makes aldosterone synthase inhibition one of the more interesting emerging therapeutic strategies in hypertension.

But There Is an Important Safety Issue

Potassium matters.

Hyperkalemia occurred more often among patients receiving baxdrostat than among those receiving placebo.

That is clinically important because many patients with resistant hypertension also have conditions that can increase hyperkalemia risk, including chronic kidney disease or use of other medications affecting the renin-angiotensin-aldosterone system.

Clinical Takeaway

Baxdrostat provides important evidence that directly targeting aldosterone synthesis can meaningfully lower blood pressure in uncontrolled and resistant hypertension.

However, clinicians should distinguish promising phase 3 efficacy data from established long-term cardiovascular-outcome evidence.

Lowering blood pressure is important.

Demonstrating long-term effects on cardiovascular events is another question.

7. KARDIA-2: RNA Interference Comes to Hypertension

Perhaps the most technologically novel development in hypertension treatment is zilebesiran.

Zilebesiran is an investigational small interfering RNA therapy designed to reduce hepatic production of angiotensinogen, an upstream component of the renin-angiotensin system.

Instead of taking another oral antihypertensive medication every day, the concept raises the possibility of long-duration blood pressure control following an injection.

The KARDIA-2 randomized phase 2 trial evaluated a single subcutaneous dose of zilebesiran added to background therapy with indapamide, amlodipine, or olmesartan.

Additional blood pressure reductions were observed at three months compared with placebo across the treatment cohorts.

The effects persisted for months in many participants.

That raises an intriguing possibility:

Could long-acting therapies eventually reduce one of the most persistent problems in hypertension treatment—daily medication adherence?

Possibly.

But we’re not there yet.

Important Limitations

Zilebesiran remains investigational.

KARDIA-2 was a phase 2 study rather than a cardiovascular-outcomes trial.

The trial also excluded some higher-risk patients, which limits how broadly the findings can be generalized.

Adverse events including hyperkalemia, hypotension, and acute kidney failure occurred more often with zilebesiran than placebo, although most were mild and resolved.

Clinical Takeaway

RNA interference represents a fascinating potential new approach to hypertension.

But clinicians should view zilebesiran as an emerging therapy under investigation, not as an established replacement for conventional antihypertensive treatment.

What Does the 2025 Guideline Recommend in Practice?

Landmark trials are useful only if clinicians can translate them into patient care.

The 2025 U.S. guideline provides a practical framework.

Blood Pressure Goal

For most adults receiving treatment, the overarching target is:

<130/80 mm Hg

Individual circumstances still matter, particularly in patients with limited life expectancy, those requiring institutional care, pregnancy, and other situations requiring modified treatment decisions.

Lifestyle Intervention

Lifestyle modification remains foundational.

Recommended approaches include:

• Achieving or maintaining a healthy weight
• A heart-healthy dietary pattern such as DASH
• Reducing dietary sodium
• Appropriate dietary potassium intake
• Regular physical activity
• Reducing or eliminating alcohol intake
• Stress management

Lifestyle treatment isn’t something clinicians should mention briefly before prescribing medication.

It is part of hypertension therapy.

When Should Medication Be Started?

The 2025 guideline recommends antihypertensive medication, in addition to lifestyle intervention, for adults with average blood pressure of at least 140/90 mm Hg.

Medication is also recommended beginning at 130/80 mm Hg for selected patients with cardiovascular disease, previous stroke, diabetes, chronic kidney disease, or sufficiently elevated predicted cardiovascular risk.

For lower-risk adults with blood pressure remaining at least 130/80 mm Hg, medication may be appropriate if blood pressure remains elevated after an initial period of lifestyle intervention.

This is where modern cardiovascular risk assessment becomes important.

Stage 2 Hypertension: Think Combination Therapy

For adults with stage 2 hypertension, the guideline favors initiating two first-line antihypertensive agents from different classes, preferably as a single-pill fixed-dose combination when appropriate.

Why?

Because achieving control often requires more than one medication, and reducing pill burden can support adherence.

Home Blood Pressure Monitoring Matters

Office measurements provide only part of the picture.

Home blood pressure monitoring can help clinicians:

• Assess treatment response
• Identify white-coat hypertension
• Identify masked hypertension
• Adjust therapy
• Engage patients in treatment

But measurement quality matters.

The device should be appropriate, and patients should understand how to measure blood pressure correctly.

The 2025 guideline specifically cautions against relying on cuffless devices such as smartwatches for accurate blood pressure measurement until adequate precision and reliability have been demonstrated.

Hospitalists Need to Distinguish Chronic Hypertension From Hypertensive Emergency

Blood pressure management becomes especially important in the hospital.

An inpatient blood pressure of 190/100 mm Hg can look alarming.

But the number alone does not define a hypertensive emergency.

The central question is whether severe hypertension is accompanied by acute target-organ damage.

That distinction changes management.

Hospitalists should evaluate the clinical context rather than reflexively treating every elevated inpatient blood pressure reading as an emergency.

Potential contributors to transient inpatient hypertension can include:

• Pain
• Anxiety
• Medication interruption
• Withdrawal
• Volume abnormalities
• Acute illness
• Measurement technique

Aggressively lowering an asymptomatic elevated blood pressure simply because the number looks uncomfortable can expose patients to harm.

The patient matters more than the monitor.

Resistant Hypertension: Slow Down Before Adding Drug Number Four

When a patient’s blood pressure remains uncontrolled on multiple medications, adding another prescription is tempting.

First ask why control has not been achieved.

Review:

• Measurement technique
• Home readings
• Medication adherence
• Medication doses
• Drug combinations
• Sodium intake
• Alcohol use
• NSAIDs and other BP-raising medications
• Obstructive sleep apnea
• Primary aldosteronism
• Renovascular disease
• Kidney disease
• Other secondary causes

Only after confirming true resistant hypertension should clinicians move systematically through additional therapy.

PATHWAY-2 and newer aldosterone-focused research make this an especially active area of hypertension medicine.

Seven Trials, Seven Practical Lessons

The major hypertension studies tell a coherent story.

SPRINT: More intensive blood pressure control can reduce cardiovascular events in appropriately selected high-risk patients.

STEP: Many older adults can also benefit from more intensive treatment when therapy is individualized.

SSaSS: Dietary interventions can influence meaningful cardiovascular outcomes, but potassium-based strategies require appropriate patient selection.

CLICK: Chlorthalidone can lower blood pressure even in advanced CKD, challenging older assumptions about thiazide-like diuretics.

PATHWAY-2: Spironolactone is an important therapy for true resistant hypertension when appropriate.

BaxHTN: Aldosterone synthase inhibition has demonstrated significant blood-pressure lowering in phase 3 research.

KARDIA-2: RNA interference targeting angiotensinogen may eventually offer long-duration hypertension treatment, but it remains investigational.

Together, these trials show how rapidly hypertension treatment continues to evolve.

Why These Trials Matter for Hospitalists

Hypertension is often considered an outpatient disease.

Hospitalists still encounter its consequences every day.

We care for patients with:

• Stroke
• Acute coronary syndromes
• Heart failure
• Chronic kidney disease
• Acute kidney injury
• Atrial fibrillation
• Aortic disease
• Hypertensive emergencies

We also make decisions about whether to continue, hold, restart, or modify antihypertensive therapy during acute illness.

That makes hypertension knowledge relevant to inpatient medicine even when long-term blood pressure management ultimately returns to the outpatient clinician.

Current CME Getaways curricula include hypertension and hypertensive emergencies as part of broader cardiovascular and hospital-medicine education.

For clinicians who want structured updates across hypertension, heart failure, atrial fibrillation, acute coronary syndromes, anticoagulation, kidney disease, and other common inpatient problems, Hospitalist CME provides dedicated continuing education focused on practical hospital medicine.

Landmark Trials Are Why Continuing Medical Education Matters

Hypertension illustrates how quickly a familiar area of medicine can change.

A clinician trained before SPRINT entered practice with a different understanding of optimal blood pressure targets.

CLICK challenged a familiar assumption about thiazide-like diuretics in advanced CKD.

PATHWAY-2 strengthened the evidence supporting spironolactone in resistant hypertension.

BaxHTN introduced phase 3 evidence for a new pharmacologic strategy.

KARDIA-2 demonstrated that RNA interference can produce sustained blood pressure reductions for months after a single dose in a clinical trial.

And the 2025 hypertension guideline has now integrated evolving evidence into a new framework for practice.

This is why continuing medical education matters for hospitalists and other healthcare professionals.

Medicine does not stand still.

Neither can medical education.

Final Thoughts

Modern hypertension management is moving away from simplistic rules.

It is not simply:

High number = add medication.

Effective management requires clinicians to think about:

• Accurate blood pressure measurement
• Overall cardiovascular risk
• Appropriate treatment targets
• Lifestyle intervention
• Medication adherence
• Comorbid disease
• Secondary causes
• Kidney function
• Electrolytes
• Treatment tolerance
• Home blood pressure measurements
• Patient preferences

Landmark trials such as SPRINT, STEP, SSaSS, CLICK, PATHWAY-2, BaxHTN, and KARDIA-2 have each contributed an important piece of that framework.

The 2025 hypertension guideline brings much of that evidence into contemporary practice.

For clinicians, the lesson is straightforward:

Know the evidence, understand the patient population studied, and apply the findings to the individual patient rather than treating a blood pressure number in isolation.

Explore upcoming Hospitalist CME conferences for evidence-based updates in hypertension, cardiovascular medicine, and other important areas of inpatient care.