Cardiovascular Risk Classification

Conducting a comprehensive risk assessment

• In adults without known CVD, a comprehensive assessment of cardiovascular risk includes
• consideration of the following:
  • Modifiable risk factors
    • Smoking status
    • Blood pressure
    • Serum lipids
    • Waist circumference and Body Mass Index (BMI)
    • Nutrition
    • Physical activity level
    • Alcohol intake.
  • Non-modifiable risk factors
    • Age and sex
    • Family history of premature CVD
    • Social history including cultural identity, ethnicity and socioeconomic status.
  • Related conditions
    • Diabetes
    • Chronic Kidney Disease (albuminuria ± urine protein, eGFR)
    • Familial hypercholesterolaemia
    • Evidence of atrial fibrillation (history, examination, electrocardiogram).

Absolute cardiovascular disease (CVD) risk assessment 

• The calculator’s “engine” is the NZ-derived PREDICT equation, Developed from contemporary, real-world data from over 400,000 patients in New Zealand, recalibrated for Australia, and it estimates 5-year risk of first fatal or hospitalised CVD event.
• Optional Risk Factors:
  • The calculator allows for additional risk considerations, including:
    • Geographical Area: Determined by residential postcodes, indicating area-level socioeconomic deprivation.
    • Atrial Fibrillation: Inclusion as an independent risk factor.
    • Type 2 Diabetes: With additional considerations for:
      • HbA1c levels
      • Duration since diabetes diagnosis (in years)
      • Urinary albumin-to-creatinine ratio (uACR)
      • Estimated glomerular filtration rate (eGFR)
      • Body Mass Index (BMI)
      • Use of insulin within the previous 6 months
    • Current Medications:
      • Blood pressure-lowering medications
      • Lipid-modifying medications
      • Antithrombotic medications
• Risk Estimation:
  • The calculator provides a 5-year risk estimate for cardiovascular events, categorized as follows:
    • High Risk: ≥10% risk over 5 years
    • Intermediate Risk: 5% to <10% risk over 5 years
    • Low Risk: <5% risk over 5 years
• These categories differ from the 2012 Guidelines for managing absolute CVD risk, as recalibration has resulted in distinct percentile ranges for high, intermediate, and low classifications.
• Limitations:
  • The Aus CVD Risk Calculator is not validated for use in individuals with type 1 diabetes, as it may yield inaccurate estimates in this population.
• Definition of Cardiovascular Disease (CVD):
  • For this guideline, ‘cardiovascular disease’ encompasses the following conditions:
    • Myocardial infarction (MI)
    • Angina
    • Other coronary heart disease (CHD)
    • Stroke
    • Transient ischaemic attack (TIA)
    • Peripheral vascular disease
    • Congestive heart failure
    • Other ischemic CVD-related conditions

Target population

• NOT known to have CVD or to be at
• NOT clinically determined high risk

	aged
All people	45-79 years
People with diabetes	35-79 years
First Nations people	30-79 years
First Nations people	18-29 years – CVD risk factors should be screened, as part of an annual health check (or opportunistically) or at least every 2 years : – smoking status – blood pressure (BP) – blood glucose level or glycated haemoglobin (HbA1c) – estimated glomerular filtration rate (eGFR) – serum lipids – urine albumin-to-creatinine ratio (uACR) – history of familial hypercholesterolaemia (FH).1

Clinically determined high risk: manage as high risk….

Group	Specific threshold that triggers automatic high-risk classification
Established cardiovascular disease (secondary prevention)	Any previous MI, angina stroke/TIA peripheral arterial disease coronary or carotid revascularisation → guideline moves straight to secondary‐prevention management the risk calculator is not used. Australian Prescriber
Moderate-to-severe chronic kidney disease	EITHER sustained – eGFR < 45 mL/min/1.73 m² OR – persistent albumin-creatinine ratio > 25 mg/mmol (men) or > 35 mg/mmol (women)
Confirmed familial hypercholesterolaemia (FH)	Clinical (e.g. Dutch Lipid Clinic Network score ≥ 6) or genetic (most common inherited cause of premature CHD, with a prevalence of 1 in 250)

The Variables (1st step):

Mandatory
Variable	Application
Age	validated for adults aged 30 to 79 years.
Sex	sex at birth – (there is currently insufficient data to stratify risk for people who are intersex or non-binary sex)
Smoking status	Choose from three categories: never smoked/ previously smoke/ currently smokes
Blood pressure (BP)	Systolic blood pressure (SBP) in mmHg. –        Use the average of the last two seated, in-clinic BP measurements. –        Convert home and ambulatory BP readings to in-clinic equivalents before entering into the calculator.
Cholesterol	Ratio of total-cholesterol : HDL-cholesterol Use most recent measurements (fasting or non-fasting).
Diabetesa (type 2 only)	status: YES or NO
CVD medicines	• Any BP-loweringmedicines • lipid-modifying medicines • antithrombotic medicines taken in the past 6 months Lipid-modifying medicines – atorvastatin, fluvastatin, pravastatin, simvastatin, acipimox, bezafibrate, cholestyramine, clofibrate, colestipol, ezetimibe, ezetimibe with simvastatin, gemfibrozil and nicotinic acid. BP-lowering medicines – angiotensin converting enzyme inhibitors, betablockers, thiazide, angiotensin II receptor blockers and calcium channel blockers. Antithrombotic medicines – aspirin, clopidogrel, dipyridamole, prasugrel, ticagrelor, ticlopidine, warfarin, dabigatran, phenindione and rivaroxaban.

Additional diabetes type 2-specific variables (not compulsory, but gives more accurate assessment of risk)
Time since diagnosis of diabetes	Enter time in years.
Glycated haemoglobin (HbA1c)	Enter HbA1c in mmol/mol or % (single non-fasting).
uACRb	Enter urine albumin-creatinine ratio (uACR) (measured in mg/mmol).
eGFRb	Enter eGFR in mL/min/1.73m2
Body mass index(BMI)	Measure weight in kilograms and height in metres.  Calculate BMI: kg/m2.
Insulin	Record use of insulin in the 6 months before risk assessment.

Non- Mandatory
Postcode	Postcode is used to calculate Socio-Economic Indexes for Areas (SEIFA) quintile, and under the discretion of the clinician, may be manually adjusted to better reflect the socioeconomic status of individual patients.
Medical history of atrial fibrillation	Known history of electrocardiogram (ECG) confirmed atrial fibrillation: YES or NO. Both paroxysmal and persistent AF are included in the definition of AF.

 Consider reclassification factors (step 2)

Factor	Potential to reclassify upward or downward
Ethnicity	↑ or ↓
Family history of premature CVD	↑
Chronic kidney disease	↑
Severe mental illness	↑
Coronary artery calcium score	↑ or ↓

reclassify downward

• Coronary artery calcium score of 0
• East Asian ethnicity (Chinese, Japanese, Korean, Taiwanese, or Mongolian ethnicities)

reclassify upward

• Coronary artery calcium score > 99 units, or ≥ 75th percentile for age and sex
• Ethinicity
  • First Nations people
  • Māori
  • Pacific Islander
  • South Asian ethnicity (Indian, Pakistani, Bangladeshi, Sri Lankan, Nepali, Bhutanese or Maldivian ethnicities)
• Family history of premature coronary heart disease (CHD) or stroke in a first-degree
  • female relative aged <65 years or
  • male relative aged <55 years
• Chronic kidney disease
  • eGFR 45–59mL/min/1.73m2 and/or
  • persistent uACR
    • 2.5–25mg/mmol (men) or
  • 3.5–35mg/mmol (women)
• Severe mental illness (current or recent mental health condition requiring specialist treatment, whether received or not, in the 5 years prior to the CVD risk assessment.)

Risk category	Estimated  5‑year CVD riska	Management	Reassessment interval
High	≥10%	Encourage, support and advise a healthy lifestyle.b Prescribe ·        blood pressure-lowering ·        lipid-modifying pharmacotherapy.c	Formal reassessment of CVD risk is not generally required. High-risk status requires clinical management and follow up supported by ongoing communication.
Intermediate	5% to <10%	Encourage, support and advise a healthy lifestyle.b   Consider blood pressure-lowering and lipid-modifying pharmacotherapy, depending on clinical context.	Reassess risk every 2 years if not currently receiving pharmacotherapy to reduce CVD risk. Assess sooner if close to the threshold for high risk, if CVD risk factors worsen, or new CVD risk factors are identified. For First Nations people, reassess every year as part of an annual health check (or opportunistically) or at least every 2 years.
Low	<5%	Encourage, support and advise a healthy lifestyle.b   Pharmacotherapy is not routinely recommended.	Reassess risk every 5 years. Assess sooner if close to the threshold for intermediate risk, if CVD risk factors worsen, or new CVD risk factors are identified.   For First Nations people, reassess every year as part of an annual health check (or opportunistically) or at least every 2 years.

NOT built into the 2023 Aus CVD Risk Calculator algorithm

Category	Examples not in the numeric equation
Strong family/genetic factors	• Lipoprotein(a) •Apo B •polygenic risk scores
Pregnancy-related history	• Preeclampsia • eclampsia • gestational hypertension/diabetes • pre-term birth • stillbirth/miscarriage history
Inflammatory / systemic disease	• Rheumatoid arthritis • systemic lupus • psoriasis • HIV • chronic inflammatory bowel disease • chronic periodontitis
Metabolic Syndrome	• waist circumference/central obesity not included (rest are included) • BMI in non-diabetics
laboratory measures	• BMI & waist circumference in non-diabetics • Triglycerides (other than via TC:HDL ratio) • Serum urate, CRP, homocysteine
Subclinical atherosclerosis tests	• carotid intima-media thickness • ankle–brachial index • retinal microvascular changes
Lifestyle factors	• Physical inactivity • poor diet quality • high alcohol intake • obstructive sleep apnoea • chronic psychosocial stress • social isolation
Diabetes subtype	• Type 1 diabetes (calculator validated only for type 2)
Other clinical signs	• Erectile dysfunction • non-alcoholic fatty liver disease • chronic lung disease (COPD) • autoimmune thyroid disease

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Practice Points – Communicating Cardiovascular Risk

1. Presenting CVD Risk in Patient-Friendly Formats

• Use percentage-based language:
  • e.g., “You have a 15% chance of having a heart attack or stroke in the next 5 years.”
• Translate to frequency-based format:
  • e.g., “15 out of 100 people like you will experience a heart event in 5 years.”
• Incorporate visual aids:
  • Use 100-person diagrams or icon arrays to show the proportion at risk.

2. Considering Health Literacy and Receptivity

• Assess patient understanding:
  • e.g., “How comfortable are you with understanding medical risks?”
• Adapt to learning style:
  • Visual learners: charts, infographics
  • Auditory learners: verbal repetition and open discussion
• Offer decision aids:
  • Booklets, smartphone apps, printed visuals
  • Use tools like the Australian Absolute CVD Risk Calculator

3. Linking Risk to Personal Experiences

• Make it personally relevant:
  • e.g., “Your brother’s recent high BP diagnosis increases your genetic risk.”
• Consider life stage:
  • e.g., “Optimising heart health now is important for a healthy pregnancy.”

4. Discussing and Contextualising CVD Risk Factors

• Identify modifiable risks:
  • e.g., smoking, obesity, alcohol, sedentary lifestyle
• Explain impact:
  • e.g., “Quitting smoking can halve your CVD risk within a year.”
• Promote achievable changes:
  • e.g., “Losing 5% of your body weight can improve BP and reduce risk.”

5. Reinforcing Risk Information Over Time

Use repeated conversations:

• Reassess risk at follow-up visits; reinforce key messages.

• Track and re-evaluate risk:
  • Update assessments with lifestyle changes or treatment.
  • Maintain engagement through encouragement and review.

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Coronary Artery Calcium (CAC) Score

Purpose and Function

• Measures the burden and density of coronary artery calcification, reflecting atherosclerotic plaque load.
• Reported in:
  • Agatston units (AU) – absolute score.
  • Percentiles – relative to age- and sex-matched population.

Limitations

• Does not assess degree of luminal stenosis.
• non-calcified, lipid-rich “vulnerable” soft plaque is invisible on a plain CAC scan
  • Soft plaque carries the highest rupture risk.
  • Imaging soft plaque
    • Requires CT coronary angiography (CTCA) or (less commonly) coronary MRI.
    • CAC is therefore not a perfect rule-out test, but its strong negative predictive value (<1 % 5-yr event rate when CAC = 0) makes missed “pure soft-plaque” events uncommon in truly asymptomatic people.
    • Prevalence with age
      • With advancing age plaques tend to calcify; purely non-calcified plaques are actually more prevalent in younger high-risk adults, and mixed plaques dominate after mid-life.
      • Hence a CAC = 0 in a 35-year-old smoker is less reassuring than in a 65-year-old non-smoker.
• Not appropriate as a standalone test in symptomatic individuals (e.g. chest pain, suspected angina).

Clinical Utility

• Enhances individualised CVD risk stratification, especially in low-to-intermediate risk individuals.
• May guide decisions on initiation or intensification of pharmacological therapies.
• High negative predictive value – a score of zero is associated with low near-term cardiovascular risk.

Age Considerations

• CAC increases with age, including in healthy individuals.
• Limited discriminative value in patients >75 years, where high CAC scores are common and less specific.

Normal CAC Score (Zero)

Re-testing may be considered in 2–5 years to monitor risk progression.

• Approximately 25% of patients with an initial score of zero will develop CAC within 5 years.

When Not to Use CAC Scoring

• Known coronary heart disease, including:
  • Previous MI
  • Prior revascularisation (PCI or CABG)
  • Established high CVD risk (e.g. ≥15% 5-year risk per Australian guidelines)
• Population screening of asymptomatic individuals without risk factors.

Indications for CAC Testing – Clinical Scenarios

Clinical Situation	CAC Testing	Rationale / Implications
Population screening for CVD	Not recommended	Low yield in asymptomatic general population.
High CVD risk (≥10% 5-year risk)–	Not recommended	– familial hypercholesterolaemia – LDL ≥ 5 mmol/L – eGFR < 45 mL/min – existing CVD Would not alter management – treatment already indicated.
Known CVD (e.g. MI, stents, CABG)	Not recommended	Does not guide further risk stratification or management. proceed to diagnostic imaging (CTCA, stress testing, angiography)
Age > 75 yrs	Not recommended	Not recommended
Low or intermediate CVD risk + additional risk factors	May be considered if available	Can assist reclassification: – CAC = 0 → lower risk – CAC >99 AU / >75th percentile → higher risk
Considering changes to preventive therapy	May be considered	Can support shared decision-making and treatment adjustments.
Previous CAC score of zero	Re-test in 2–5 years	Allows risk reassessment; ~25% develop CAC over 5 years.

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Why use a CAC score before starting a statin?

1. Risk re-classification in the “grey-zone”
   For borderline (5–10 %) or intermediate (10–15 %) 5-year risk patients a CAC scan can shift decisions:
   • CAC = 0 → event rate < 1 % in 5 years; reasonable to defer statin and re-scan in 3–5 years if no other very-high-risk features.
   • CAC 1–99 → favours statin in age ≥ 55 y or if score ≥ 75th percentile.
   • CAC ≥ 100 or ≥75th percentile → treat with statin at any age. (Australian CSANZ & RACGP / Heart-Foundation guidance; ACC/AHA 2018 cholesterol guideline RACGP American College of Cardiology)
2. Shared decision-making – a visible number helps patients balance life-long therapy against perceived benefit.
3. Low radiation (≈1 mSv) and fast (< 5 min) outpatient test.
4. Explain that a zero score ≠ zero risk
   • it just means very low short-term risk
   • healthy lifestyle and periodic reassessment remain essential.

Not indicated if risk is already high (>15 %), risk is very low, or the patient has established CVD – treatment is already clear.

After statin initiation → do not use changes in the absolute CAC score to judge treatment success or failure. Focus on LDL-C targets, lifestyle, and symptom review.’

• Statins increase plaque calcium density, which converts a “soft-plaque”, rupture-prone lesion into a more stable, fibrotic–calcific cap.
• Multiple cohort and randomised CTCA studies confirm that this paradoxical rise in CAC correlates with lower rates of acute coronary syndrome, not higher. American College of Cardiology

If you need anatomical follow-up (e.g. strong family history, very high Lp(a)) → CT coronary angiography is a better tool to track non-calcified plaque.

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Non-Calcified (Soft) Atherosclerotic Plaque

Composition

• Predominantly composed of a lipid-rich necrotic core
• Contains activated inflammatory cells (e.g. macrophages, T-lymphocytes)
• Often associated with a thin fibrous cap, making it more prone to rupture
  (Ref: Virmani R et al., Circulation, 2000)

Imaging Characteristics

• Poorly visualised on non-contrast CT due to low radiodensity
• Coronary CT angiography (CCTA) with contrast can improve detection but may still underestimate volume
• Cardiac MRI and intravascular ultrasound (IVUS) or optical coherence tomography (OCT) offer better characterisation of plaque composition
  (Ref: European Heart Journal 2020;41(3):349–355)

Rupture Risk and Clinical Significance

• Higher propensity for rupture than calcified plaque
• Plaque rupture can result in thrombus formation, leading to:
  • Acute coronary syndromes (ACS)
  • Sudden cardiac death
• Rupture-prone plaques are termed “vulnerable plaques”, often asymptomatic until rupture
  (Ref: Naghavi M et al., Circulation, 2003)

Epidemiology

• Prevalent in middle-aged to older adults, especially men
• Can occur in younger individuals with clustering of cardiovascular risk factors

Associated Cardiovascular Events

• Strongly correlated with:
  • Myocardial infarction (MI)
  • Ischaemic stroke
• Histopathological studies confirm the role of non-calcified plaques in acute thrombotic events
  (Ref: Libby P, Nature, 2002)

Major Risk Factors

• Dyslipidaemia:
  • Elevated low-density lipoprotein cholesterol (LDL-C)
  • Elevated triglyceride-rich lipoproteins
• Hypertension
• Diabetes mellitus (particularly if poorly controlled)
• Cigarette smoking
• Sedentary lifestyle and poor dietary patterns
• Obesity, especially central adiposity
• Male sex (higher risk earlier in life)
• Advancing age
• Positive family history of premature CVD
• Chronic low-grade inflammation (e.g., elevated hs-CRP)

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Statin Therapy in the Elderly (>79 years)

Initiation Considerations:

• Clinical judgment incorporating:
  • Potential benefit vs. risk
  • Life expectancy and co-morbidities
  • Patient’s values and preferences

Indications to Continue Statin in >79 years:

• Established coronary artery disease
• High coronary calcium score
• ABPI < 0.9
• hsCRP > 2 mg/L
• Consider even without above if NNT justifies (NNT = 83 over 3–4 years to prevent 1 MI; Savarese 2013, JACC)

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Ankle Brachial Pressure Index (ABPI)

Definition:

• Ratio of ankle systolic BP to brachial systolic BP

Interpretation:

• <0.9: Suggests peripheral artery disease (PAD)
• >1.4: Likely calcified, non-compressible arteries (still often PAD)

Clinical Use:

• Associated with coronary and cerebrovascular disease
• Not recommended for routine population screening
• Abnormal results warrant CVD risk factor optimisation

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High-Sensitivity C-Reactive Protein (hsCRP)

Definition:

• Liver-produced inflammatory marker
• Detected down to 0.3 mg/L

Normal/Abnormal Values:

• <3 mg/L: Normal
• >2 mg/L: May indicate increased CVD risk

Clinical Relevance:

• Modestly predictive of CV events
• Limited utility as a standalone screening test

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24-Hour Ambulatory Blood Pressure Monitoring (ABPM)

(Australian & International hypertension guidelines, e.g. 2023 NHFA/RACGP, ESC/ESH 2023)

1 What ABPM actually does

Aspect	Key points
Device & schedule	Automatic oscillometric cuff records BP every 15-30 min while awake and every 30-60 min during sleep over a ≥ 24-h period.
Outputs	• 24-h mean SBP/DBP   • Daytime mean   • Night-time mean   • Hour-by-hour graph   • Aim for ≥ 70 % valid readings
Clinical value	• Gold standard for diagnosing hypertension outside the clinic   • Best predictor of LV hypertrophy, stroke, CKD progression.

Indications

(Based on 2023 NHFA / RACGP Australian hypertension guidelines, ESC/ESH 2023, and NICE NG 136)

Clinical Scenario	Why ABPM Adds Value
Confirming a new diagnosis of hypertension when clinic BP ≥ 140/90 mm Hg (or ≥ 130/80 mm Hg in high-risk patients)	Removes white-coat effect; provides true 24-h mean BP before lifelong therapy
Suspected white-coat hypertension (persistently high office BP but low cardiovascular risk and normal or borderline home/automated kiosk readings)	Avoids unnecessary treatment; guides lifestyle-only follow-up
Suspected masked hypertension (normal office BP but high CV risk, target-organ damage, or elevated home/kiosk readings)	Detects hidden risk; evidence shows masked HTN carries the same event rate as untreated clinic HTN
Apparent resistant hypertension (clinic BP above target on ≥ 3 drugs including a diuretic)	Distinguishes true resistance from poor adherence or white-coat effect; helps titrate night-time dosing
Marked BP variability or episodic hypertension (e.g. pheochromocytoma, autonomic dysfunction, anxiety spikes)	Captures paroxysmal peaks that single readings miss
Assessment of nocturnal BP patterns (non-dipping, reverse-dipping, extreme-dipping, nocturnal hypertension)	Informs stroke/CKD risk and supports chronotherapy (bed-time dosing) or sleep-apnoea work-up
Hypertension in high-risk groups: • Diabetes • Chronic kidney disease • Pregnancy (specialised devices) • Children/adolescents	Clarifies true burden and guides tighter targets
Evaluation after treatment changes (new drug, dose timing, chronotherapy)	Determines 24-h control and early-morning surge; fine-tunes regimen
Suspected hypotensive symptoms on medication (dizziness, falls, syncope)	Documents over-treatment, post-prandial or night-time hypotension
Occupation-specific clearance (pilots, commercial drivers, emergency-services personnel) when borderline clinic readings could affect licensing	Provides objective evidence for fitness-to-work decisions

2 Diagnostic uses & thresholds

Scenario detected by ABPM	Threshold* (mm Hg)	Clinical implication
Sustained hypertension	24-h ≥ 130/80 or Daytime ≥ 135/85 or Night-time ≥ 120/70	Start/adjust lifelong therapy & risk management
White-coat hypertension	Office ≥ 140/90 but 24-h & daytime < thresholds	Lifestyle advice yearly review – 30 % progress to true HTN in 4–5 yr
Masked hypertension	Office < 140/90 but 24-h or daytime ≥ thresholds	Treat as sustained HTN – CVD risk equals untreated office HTN
Nocturnal BP disorders	<10 % fall (“non-dip”) or rise (“reverse-dip”) or >20 % fall (“extreme dip”) vs daytime	Non-dip/reverse-dip → ↑ stroke, CKD, HF; extreme-dip → ↑ ischaemic events in elderly – consider bedtime dosing of antihypertensives
*Australian & ESC/ESH diagnostic cut-offs.

Typical ABPM vs clinic difference: mean daytime SBP is ≈ 5–10 mm Hg lower than office readings; this is normal and built into the thresholds.

3 How to read an ABPM report in practice

1. Check data quality – ≥ 70 % successful readings, plausible wake/sleep times.
2. Confirm diagnostic category – compare means with thresholds above.
3. Look at the day-night profile – calculate % dip
4. Identify peaks – early-morning surge (> 50 mm Hg rise) suggests higher stroke risk.
5. Cross-check with symptoms/med timing – dizziness, nocturia, etc.

4 Strengths & limitations

Strengths	Limitations
• Superior prediction of CV & renal events versus office BP or Home BP (META-analysis HR ≈ 1.4 per 10 mm Hg 24-h SBP). • Unmasks white-coat & masked HTN. • Guides chronotherapy (bed-time dosing).	• Cost ($50–120 hire), limited availability. • Discomfort / sleep disturbance. • Not reimbursed everywhere. • Contra-indicated in atrial fibrillation (oscillometric inaccuracy) & morbidly obese arms.

Therefore, the statement “adds little beyond standard office BP” is incorrect – ABPM adds substantial prognostic and diagnostic value.

5 Clinical actions based on ABPM results

Finding	Management suggestions
Sustained or masked HTN	Lifestyle + drug therapy to reach < 130/80 clinic (or < 125/75 ABPM in high-risk).
Non-dipping / reverse-dipping	• Exclude sleep apnoea, CKD, autonomic neuropathy. • Consider shifting ≥ 1 antihypertensive to bedtime.
White-coat HTN	Reinforce lifestyle re-check ABPM or Home BP annually higher vigilance if ≥ 135/85 daytime.
Resistant pattern (> 130/80 despite ≥ 3 drugs)	Confirm adherence, exclude secondary causes, consider specialist referral.

Note = Home BP monitoring (HBPM) is an acceptable alternative when ABPM is unavailable, but ABPM remains the reference standard for diagnosis and risk prediction.