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Managing inadequate response to treatment Failure of response to initial therapy or loss of initial BP control occurs due to a wide range of prescriber-related, patient-related and drug-related factors. First, check that treatment has followed recommended prescribing guidelines for achieving BP targets (see Drug treatment, page 19).
If BP remains above target despite maximal doses of at least two appropriate agents after a reasonable period, consider the following potential explanations: • non-adherence to therapy, including recommended • secondary hypertension due to an undiagnosed • use of medications that may increase BP (Table 4,
• treatment resistance due to sleep apnoea• undisclosed alcohol or recreational drug use • unrecognised high salt intake (particularly in patients taking ACE inhibitors or angiotensin II receptor antagonists) • ‘white coat’ hypertension• BP measurement artefacts e.g. inadequate cuff size• volume overload, especial y with CKD.
In some patients (e.g. the very elderly), recommended target levels may not be tolerable or achievable. In this case, comorbidities and individual cardiovascular risks should be considered when planning management.
Heart Foundation Guide to management of hypertension 2008 Selecting an antihypertensive agentFor all major antihypertensive drug classes, the patients treated with beta-blockers (mainly atenolol) beneficial effect is mainly due to BP lowering, compared with those treated with other classes of irrespective of their mechanism of action.
In uncomplicated hypertension, the following classes For patients with stable, well-controlled hypertension of antihypertensive agents are equally effective for who are already taking a beta-blocker, it is reasonable first-line use, both in initial and maintenance therapy (Figure 3 – see fold out):
The initial drug choice should be based on: • ACE inhibitors (or angiotensin II receptor antagonists)* • the patient’s age (Figure 3 – see fold out)
• dihydropyridine calcium channel blockers • the presence of associated clinical conditions or end- • low-dose thiazide diuretics (for patients aged 65 organ damage (Table 3 – see fold out)
• the presence of other co-existing conditions that Thiazide diuretics have been associated with increased either favour or limit the use of particular drug classes risk of new-onset diabetes and should be used with (Table 7)
caution in patients with glucose intolerance and/or • potential interactions with other drugs metabolic syndrome.46 The use of thiazide diuretics as first-line therapy should be limited to older patients, • implications for adherence (Table 8)
in whom the benefits of managing isolated systolic hypertension and preventing stroke with these agents are likely to outweigh the risk of diabetes onset.
Most classes of antihypertensive agents used as monotherapy lower BP by a similar average amount. Beta-blockers are no longer recommended as first- However, the individual response to each agent is line therapy in uncomplicated hypertension because of the increased risk of developing diabetes and the recently described trend towards worse outcomes in *ACE inhibitors and angiotensin II receptor antagonists have been shown to be equally efficacious in prevention of cardiovascular end points and in lowering BP.43,44,45 Attempt to reach recommended targets (Table 6 – see
Combination drug therapy will often be required to fold out). There is a direct linear relationship between
reach targets. Even if targets are not met, patients are BP and cardiovascular risk across the continuum of BP likely to benefit from any BP reduction achieved.
levels normally seen in clinical practice; lower BP levels have been associated with the strongest benefits. How to achieve target BP• Start with the lowest recommended dose of selected Combination therapy, page 24). This approach first-line agent (Table 9).
maximises antihypertensive efficacy while minimising • If the initial drug is not well tolerated, change to a adverse effects, and is recommended pending further drug of a different class, starting with the lowest evidence clarifying the role of fixed-combination • If target BP (Table 6 – see fold out) not reached
• If BP is still above target and both antihypertensive or there is no significant reduction with initial agents have been well tolerated, increase the monotherapy, add a second agent from a different dose of one agent (other than a thiazide diuretic) pharmacological class at a low dose, rather incremental y to maximal recommended dose before than increasing the dose of the first agent (see increasing the dose of the other agent.
Heart Foundation Guide to management of hypertension 2008 • Trial each dose regimen for at least 6 weeks before • Encourage full adherence to medications (Table 8)
altering doses, because a stable response to a particular dose takes at least 3–4 weeks.
• Targets may be difficult to achieve or may not be • Choose long-acting drugs to provide 24-hour efficacy tolerated in some patients (e.g. the very elderly, those with a superimposed ‘white-coat’ effect or those with • Once a combination regimen is established as long-term therapy, it may be more convenient for the patient to use a combined preparation (e.g. ACE inhibitors/thiazide diuretics, angiotensin II receptor antagonists/thiazide diuretics, ACE inhibitors/calcium channel blockers). Table 7. Choice of antihypertensive agent in patients with comorbid and associated conditions
Condition
Potentially beneficial
Potentially harmful
Contraindicated
Remodelling: ACE inhibitors, angiotensin II receptor antagonists†Rate control: nondihydropyridine calcium channel blockers, beta-blockers metoprolol controlled release): use cautiously in mild/moderate disease only Beta-blockers, clonidine, methyldopa, moxonidine antagonists (telmisartan, olmesartan, losartan) carvedilol, metoprolol controlled release), spironolactone oxprenolol, pindolol), ACE inhibitors, eplerenone Heart Foundation Guide to management of hypertension 2008 Table 7. Choice of antihypertensive agent in patients with comorbid and associated conditions (continued)
Condition
Potentially beneficial
Potentially harmful
Contraindicated
II receptor antagonists, diuretics, calcium channel blockers (before 22 weeks’ gestation), atenolol ACE inhibitors, angiotensin II receptor antagonists† (unilateral in patient with solitary kidney) Low-dose thiazide diuretics ± ACE inhibitors, eprosartan Adapted from references 19 and 48*Particular beta-blockers are now indicated in the treatment of heart failure. See the Heart Foundation Guidelines for the prevention, detection and management of chronic heart failure in Australia, 200611 (available at www.heartfoundation.org.au).
†Careful monitoring of kidney function is required if a combination of ACE inhibitors and angiotensin II receptor antagonists are used.43 ‡When used in combination with an ACE inhibitor, may be beneficial in type 2 diabetes.10 Table 8. Strategies for maximising adherence to the management plan
• Express empathy to earn the patient’s trust and • Treat the patient as a partner in management • Assess the patient’s expectations of treatment.
• Discuss treatment options and agree on an initial • Use self-measurement of BP for monitoring, where treatment plan, including how to reach target BP.
• Provide specific written instructions and patient • Consider referral for a Home Medicines Review.
• Evaluate the social and economic barriers that may • Involve the patient’s family in the therapeutic plan.
affect medication supply and storage.
• Discuss the use of compliance aids (e.g. dosette • Explain the risks and benefits of treatment, and the • Address quality-of-life issues including any new symptoms or side effects of treatment.
• Clearly explain that drug treatment will be life-long.
• Address psychosocial factors that may limit • Reassure the patient about prognosis and ability to adherence (e.g. manage depression, if present).
• Reinforce lifestyle modifications at fol ow-up visits.
Heart Foundation Guide to management of hypertension 2008 Table 9. Recommended doses for antihypertensive drugs
ACE inhibitors
5–40 mg once daily or in two equally divided doses 5–40 mg once daily or in two equally divided doses 2.5–10 mg once daily or in two equally divided doses Note Commence at the lowest dose in elderly patients and those taking diuretics.
Calcium channel blockers – dihydropyridine
5–20 mg once daily (controlled release) 10–40 mg twice daily (conventional) 20–120 mg once daily (controlled release) Notes Amlodipine and felodipine: lowest doses are recommended, particularly in the elderly. Nifedipine: long-acting formulations are preferable.
Calcium channel blockers – nondihydropyridine
180–360 mg once daily (controlled release) 120–240 mg once daily (controlled release) Angiotensin II receptor antagonists
Notes Commence at the lowest dose in elderly patients and those taking diuretics. Use with caution in those who have experienced angioedema with ACE inhibitors.
Heart Foundation Guide to management of hypertension 2008 Table 9. Recommended doses for antihypertensive drugs (continued)
Thiazide diuretics
Notes It is usually unnecessary to exceed the doses shown.
If plasma potassium concentration drops below the laboratory reference range during thiazide diuretic therapy, a potassium-sparing diuretic (e.g. amiloride 2.5–5 mg orally daily or triamterene 50 mg orally) may be prescribed in combination with the thiazide. This may not be necessary if the patient is also taking an ACE inhibitor or angiotensin II receptor antagonist.
Loop diuretics (e.g. frusemide) are not recommended as antihypertensive agents unless volume overload is present.
Beta-blockers
Metoprolol succinate (controlled release) Note Atenolol: recommended only in combination with other agents. For patients on current atenolol monotherapy, consider replacing with another beta-blocker or another drug class (due to adverse outcomes in meta-analyses of monotherapy clinical trials). Metoprolol succinate (controlled release): see approved product information for titration schedule.
Bisoprolol: see approved product information for titration schedule. Reimbursement on PBS available only for people with stable moderate-to-severe heart failure.
Notes Clonidine: rebound hypertension may occur on sudden cessationHydralazine: generally used only in combination with a beta-blocker or verapamil, which prevent reflex tachycardia. Maintenance doses above 100 mg daily are associated with increased risk of lupus-like syndrome and should not be given without determining patient’s acetylator status.
Prazosin: to avoid postural hypotension, commence at night and with low dose.
Heart Foundation Guide to management of hypertension 2008 Combination therapyAn estimated 50–75% of patients with hypertension Occasionally a combination of more than three will not achieve BP targets with monotherapy.49 For antihypertensive drugs may be required to achieve most patients, a combination of antihypertensive drugs from two or more pharmacological classes is needed. Based on the best available evidence, the most effective combination is:
(particular role in the presence of diabetes or lipid abnormalities)50 Other effective combinations include:
infarction or in people with heart (not recommended in people with glucose intolerance, metabolic syndrome, or established diabetes) Avoid the following combinations:
* ACE inhibitors and angiotensin II receptor antagonists have been shown to be equally efficacious in prevention of combined end points of cardiovascular disease death, myocardial infarction, stroke and heart failure admissions in patients at high risk due to past cardiovascular events.43 Heart Foundation Guide to management of hypertension 2008 Monitoring response to drug treatment During stabilisation, reassess response every 6 weeks Once stabilised, the interval between visits can be or as indicated; appropriate intervals vary between a lengthened, e.g. review every 3 months for the next few days and 2 months. Consider adverse effects of 12 months and 6-monthly thereafter while BP remains medications (Table 10).
stable (Figure 4 – see fold out).
Table 10. Potential adverse effects
Angiotensin
Thiazide
ACE inhibitors*
II receptor
Beta-blockers
adverse effects
diuretics
antagonists*†
blockers
+ predictable adverse effect; – clinically significant rates not reported; ±: rare reportsAdapted from reference 51 *An initial rise in serum creatinine is commonly observed after initiation of ACE inhibitors or angiotensin II receptor agonists. An increase of 30% or less is acceptable. If creatinine increases by more than 30% from baseline, consider possible contributory factors (e.g. hypovolaemia, renal artery stenosis, NSAIDs). If none present, consider ceasing treatment. Do not commence these agents if serum potassium is > 5.0 mmol/L.
ACE inhibitors and angiotensin II receptor antagonists are not nephrotoxic, but they reduce the kidney’s ability to respond to an acute reduction in renal perfusion. Their use should be temporarily suspended during any episode which may lower renal perfusion (e.g. shock or sepsis).
†Caution should be exercised in introducing angiotensin II receptor antagonists in those who have experienced angioedema with ACE inhibitors.
‡Beta-blockers do not appear to induce or worsen postural hypotension.52 Heart Foundation Guide to management of hypertension 2008 Evaluation in patients with confirmed hypertension The diagnostic process (history, physical examination • detect end-organ damage and related or comorbid clinical conditions (Table 3 – see fold out)
• identify causes of secondary hypertension.
HistoryTake a full history with particular attention to the • family history of hypertension, diabetes, dyslipidaemia, stroke, CKD or premature (before • known duration of raised BP and previous levels • ambulatory or self-measured BP levels (if known) • modifiable lifestyle risk factors: obesity, physical inactivity, smoking, excessive intake of alcohol, • previous antihypertensive therapy, efficacy and salt or saturated fats, recreational drug use • past history or current symptoms of ischaemic heart • medications (including complementary medicines) disease, heart failure, cerebrovascular disease or that raise BP (Table 4, Table 5)
• personal, psychosocial and environmental factors • past history or current symptoms that suggest CKD, that could influence the course and outcome of e.g. nocturia, dark urine (suggesting haematuria) antihypertensive care e.g. educational background, • symptoms suggestive of a condition that may cause family situation, work environment and associated secondary hypertension, e.g. phaeochromocytoma psychological stress (assess for depression, social (paroxysmal headache, sweating, palpitations), sleep isolation and quality of social support).
• history of hypokalaemia or suggestive symptoms • the presence of asthma, chronic obstructive pulmonary (e.g. muscle weakness, hypotonia, muscle tetany, disease, diabetes, dyslipidaemia, gout, erectile dysfunction, sleep apnoea or other significant il nesses Table 4. Medications that may increase BP
• Stimulants (dexamphetamine sulfate, • Haemopoietic agents (darbepoetin, epoetin) • Immunomodifiers (cyclosporin, tacrolimus) • Monoamine oxidase inhibitors: reversible Rebound hypertension may occur following abrupt (moclobemide), irreversible (phenelzine, • Non-steroidal anti-inflammatory drugs (conventional and cyclooxygenase-2 selective) *The use of monoamine oxidase inhibitors in combination with tyramine-rich foods (e.g. matured or out-of-date cheese, fermented or matured meats, yeast and soy bean extracts, and • Oral decongestants (e.g. pseudoephedrine) others) can lead to hypertensive crisis.
Adapted with permission from reference 19 Heart Foundation Guide to management of hypertension 2008 Table 5. Complementary medicines that may increase BP
Adapted with permission from reference 19 Physical examination Perform a physical examination with particular • abnormalities of the optic fundi (e.g. tortuosity, attention to the cardiovascular system, including the thickening or arteriovenous nipping of retinal arteries, retinal haemorrhages, exudates, diabetic retinopathy, • evidence of CKD (e.g. palpable kidneys) • evidence of cardiac enlargement (displaced apex, extra heart sounds), or evidence of decompensation • evidence of abnormalities of the endocrine system (basal crackles or wheeze on lung auscultation, (e.g. Cushing’s syndrome, thyroid disease) peripheral oedema, abdominal signs, e.g. pulsatile • waist circumference (cm) and/or body mass index (BMI): weight (kg) in light clothing, divided by the • evidence of arterial disease (e.g. carotid, renal or abdominal bruits, abdominal aortic aneurysm, absent femoral pulses, radiofemoral delay) Initial investigations Undertake the following investigations to assess for • Blood analysis (sodium, potassium, chloride, end-organ disease or associated clinical conditions: bicarbonate, urea, creatinine, uric acid, haemoglobin, • Dip stick testing of urine for blood and protein fasting glucose, total cholesterol, LDL-cholesterol, – If abnormal, proceed to urine microscopy. HDL-cholesterol, triglycerides, liver function tests). – If proteinuria detected (≥ 1+ on dip stick), • Electrocardiogram (ECG) to detect conduction measure 24-hour urinary protein excretion.
disturbances, arrhythmias, coronary heart disease • Assessment of microalbuminuria (highly or left ventricular hypertrophy. The presence of recommended for all patients and mandatory strain pattern (ST depression and T-wave inversion) for those with diabetes). Microalbuminuria status is associated with increased cardiovascular risk in correlates with cardiovascular risk and its presence indicates end-organ damage. – The most accurate screening test is urinary albumin/creatinine ratio on a spot urine sample. Use this method where available. – If albumin/creatinine ratio ≥ 2.0 mg/mmol (males) or ≥ 2.5 mg/mmol (females) is detected, repeat the test to confirm. – If confirmed, obtain a 24-hour urine col ection for accurate measurement.
Heart Foundation Guide to management of hypertension 2008

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