Hypertension

Target blood pressure

(NB if low BP at baseline adjust accordingly – see notes section)

The recommended target BP is <140/90 – ideally should be this before starting therapy.

Treatment can continue as long as BP<160/100*(see notes section). Above this, VEGF-i treatment should be withheld until hypertension treated. Antihypertensive therapy should be initiated/increased if BP consistently >140/90.

Refer to specific study protocol for all patients receiving VEGF-i in a clinical trial.

Measuring blood pressure

Ensure pre-existing hypertension is adequately controlled before starting treatment with VEGF-inhibitors (should be below 140/90 on most recordings at rest).
Actively monitor blood pressure throughout VEGF-inhibitor treatment.
All blood pressure (BP) recordings should be taken whilst patient is relaxed and after sitting resting for 10 minutes in a quiet place.
If elevated, BP should be repeated after 20-30 minutes of rest in a relaxed place.
If persistently elevated in the oncology clinic/ward (but not requiring immediate treatment), arrangements should be made for either home BP monitoring (see below) or confirmatory BP measurements at the GP surgery.

Community blood pressure measurements

Patients taking oral VEGF-inhibitors should be asked to purchase a home BP monitor and check their BP daily as per the home BP monitoring Patient Information Leaflet (PIL) (only accessible when connected to intranet) In the event of persistent elevated BP, the patient should contact their GP for advice on management of their BP. If grade 3 or 4 hypertension, they should also contact the on call oncology team at WGH as per advice in the PIL(only accessible when connected to intranet) If unable to purchase a home BP monitor, then:

Arrange weekly BP measurements by the GP practice nurse
Review results at next clinic/SACT visit
Use average value of all measurements to confirm a diagnosis of hypertension. Exclude outliers.

Management of hypertension during course of treatment with VEGF-i

Patients treated with VEGF-i should have their blood pressure monitored, whilst resting, before initiating therapy and with each cycle of therapy (every 2-3 weeks). Please see notes in sections above about how to monitor and check BP.

CTCAE	BP	VEGF-i action	Anti-hypertensives
Grade 1	120/80-140/90	Continue	Not required
Grade 2	140/90-160/100 or Diastoloc BP increases ≥20mmHg above baseline	Continue	Start/escalate BP treatment according to table below
Grade 3	>160/100	Withhold	Start/escalate BP treatment according to table below
Grade 4	Life-threatening consequences e.g. Malignant hypertension Encephalopathy TIA Papilloedema, retinal haemorrhage	Permanently stop	Emergency admission Discuss with on call medical team Consider HDU referral Specialist referral for management of BP

Drug choice

(more detail about each drug in later section)

NHS Scotland. East region formulary. Hypertension.

NHS Lothian hypertension guidelines (only available when connected to the intranet)

Step 1	Amlopidine 5mg (can increase to 10mg) or lisinopril 10mg
Step 2	If using amlopidine for step 1, add lisinopril 2.5mg (gradually increase dose). If using lisinopril for step 1, add amlopidine 5mg.
Step 3	Amlopidine (5-10mg) and lisinopril (optimise dose) and thiazide diuretic
Step 4	Consider referral for specialist advice or add spironolactone if serum K+ is ≤4.5 or consider doxazosin or atenolol
Step 5	Referral for specialist advice

Notes

BP should be <140/90 prior to initiating treatment with VEGF-i. If above this then optimise management of BP in conjunction with GP before first dose of VEGF-i.
*Care if low BP at start. If BP rises to ≥ 40mmHg syst or 20mmHg diast above baseline then start BP drugs. If BP rises ≥ 60mmHg syst or 30mmHg diast above start then withhold VEGF-i and start BP drugs.
Sometimes up to three or more drugs may be required to control hypertension.
Antihypertensives from different classes generally have an additive effect when prescribed together.
Submaximal doses of two drugs may result in larger falls in BP and fewer adverse effects than maximal dosages of a single drug.
The best classes of antihypertensive drugs to treat hypertension caused by VEGF-i appear to be ACE inhibitors but calcium blockers are often preferred with SACT.
Angiotensin II inhibitors (e.g. candesartan 8mg) can be used as an alternative to ACE-i in black patients, or patients intolerant of ACE-i.
As ACE-i are often discontinued during platinum therapy and not given if renal impairment, the risks and benefits of BP therapy must be evaluated, and steps 1-3 modified according to individual circumstances.

Details of drugs commonly used to treat hypertension

Points to consider when selecting and prescribing antihypertensives for an individual patient:

Class of drug	Cautions or reasons to avoid	Preferred selection if..	General cautions, contraindications and instructions
Calcium channel blockers e.g. amplopidine 5mg od (can be increased to max 10mg)	Lower extremity swelling	Elderly patients, isolated systolic hypertension	Pre-existing oedema, slow onset of action
ACE inhibitors e.g. lisinopril 5mg od at bedtime (2.5mg if on a diuretic, age >65 or mild renal impairment). Dose can be doubled every six weeks (or quicker if tolerating or if BP rising) to 10-20mg od or max of 40mg od (2.5mg, 5mg, 10mg, 20mg tabs)	Hyperkalaemia. Co-administration with drugs dependent on renal clearance e.g. cisplatin, pemetrexed Caution if renal function impaired or after nephrectomy	Left ventricular systolic dysfunction, diabetic nephropathy	Avoid if impaired renal function (risk of renal artery stenosis). Stop NSAIDs if possible. Avoid potassium-sparing diuretics or potassium supplements. Watch for cough. Arrange for serum creatinine and electrolytes to be measured weekly until stabilised.
Thiazide diuretics e.g. bendroflumethiazide 2.5mg od	Gout, hyperuricaemia, hypokalaemia, young patients (age ≤45yrs), QT interval prolonging drugs	Elderly patients, isolated systolic hypertension	Gout, documented sulfa allergy. Do not use if there is a history of angina, myocardial infarction (MI) or heart failure.
Beta blockers e.g. atenolol 25mg od	Aesthenia, malaise, fatigue, other QT interval prolonging drugs	Angina, history of myocardial infarction, anxiety	Bradycardia/heart block, diabetes (risk of hypoglycaemia), asthma/COPD, periph vasc disease
Angiotensin II inhibitors e.g. candesartan 8mg once daily (hepatic impairment 2mg od, renal impairment/intravascular volume depletion 4mg od) Increase if necessary at intervals of 4 weeks to a max. 32mg once daily. Initially 8mg (hepatic impairment 2mg, renal impairment or intravascular volume depletion 4mg) once daily, increased if necessary at intervals of 4 weeks to a max. 32mg once daily	Hyperkalaemia. Co-administration with drugs dependent on renal clearance e.g. cisplatin, pemetrexed	Intolerance of other agents, especially ACE inhibitors, left ventricular systolic dysfunction, diabetic nephropathy	Renovascular disease, peripheral vascular disease, renal impairment. Ideally reserve for patients who develop a persistent cough with ACE inhibitors. U+E should be checked within 2 weeks of commencing therapy and after any change in dose.
Other diuretics e.g. spironolactone 25mg	Hyperkalaemia K >4.5mmol/L Renal impairment	3rd line. Oedema, difficult BP control or intolerance of other drugs	Caution in renal impairment. U+E should be monitored
Alpha blockers e.g. doxazocin. Start at 1mg daily, increase after 1–2 weeks to 2mg once daily and thereafter to 4mg once daily, if necessary; max 16mg (1mg, 2mg, 4mg tabs)	Heart failure, impaired LV function, hypotension	3rd line	Doxazosin may cause first dose and postural hypotension