Assess cardiovascular risk to guide management

Assess absolute risk of a cardiovascular event

Base the decision to initiate antihypertensive drug therapy on an assessment of total cardiovascular risk as well as the blood pressure level.

Risk factors that place people at high or very high risk are

• diabetes
• symptomatic cardiovascular disease
• evidence of target organ damage
• Aboriginal, Torres Strait Islander, Maori or Pacific Islander origin.

To assess absolute cardiovascular risk in other people, use a tool such as the Australian Cardiovascular Disease Risk Charts available from The National Heart Foundation of Australia.

People at high or very high absolute risk should receive antihypertensive therapy and advice about lifestyle

The absolute benefit of antihypertensive therapy is greatest in those at highest risk. In people at high or very high risk with elevated blood pressure, initiate antihypertensive drug therapy and provide lifestyle advice.

Initiate lifestyle changes before drug therapy in people at low or medium risk

Lifestyle changes alone may be sufficient to decrease blood pressure and total risk in low-risk patients with mild hypertension. In patients at medium risk, a 3–6 month trial of lifestyle changes may reduce blood pressure and risk to acceptable levels and allow some to avoid drug therapy.

Lifestyle changes reduce blood pressure and cardiovascular risk

Encourage lifestyle changes in all patients with blood pressure ≥ 120/80 mmHg 

Lifestyle modifications can allow some people to avoid or delay the need for antihypertensive drugs. For patients receiving drug therapy, lifestyle changes may reduce the dose or number of agents required.

Ceasing smoking rapidly and substantially reduces cardiovascular risk. Refer to Prescribing Practice Review 20 for advice on smoking cessation interventions. Other lifestyle changes that reduce blood pressure and cardiovascular risk include [1–6]

• increasing physical activity
• weight loss in overweight patients
• adopting a healthy eating plan
• reducing salt intake
• moderating alcohol intake.

Guidelines for lifestyle interventions are available from the National Heart Foundation of Australia.

Initiating antihypertensive therapy

Initiate on low-dose monotherapy 

Use the lowest recommended dose of a single drug to initiate therapy. Starting treatment with a low dose helps minimise adverse effects.

Fixed-dose combination products should not be used for initiation 

Fixed-dose combination products make it difficult to titrate doses of the individual drugs or to identify the source of adverse events; they should be reserved for patients stabilised on similar doses of single agents.

A sample of desktop prescribing data indicates that 10% of first prescriptions for antihypertensive therapy are for fixed-dose combination products.[7] However, both the approved indications and PBS restricted listings for combination products specify that they should not be used for initiation.

If response is inadequate…

If the blood pressure response to a single drug is inadequate, there are several possible approaches.

• Add a low dose of a second drug.
• • Low-dose combinations are usually preferable to higher doses of a single drug.Using low doses of drugs from different classes in combination minimises the risk of dose-related adverse effects while optimising antihypertensive effects.[8] A low-dose thiazide should generally be included in any combination regimen.
• Increase the dose of the current drug.
• • Suitable when the current drug is well tolerated but the response is inadequate and may be particularly appropriate when issues such as cost or compliance are barriers to prescribing two drugs. However, this approach increases the likelihood of dose-related adverse effects and is not appropriate for thiazides, for which doses should not be increased above hydrochlorothiazide 25 mg or equivalent.
• Substitute a drug from a different class.
• • Only if the first drug produces intolerable adverse effects or adequate doses produce little response.

Try low-dose thiazides as first-line therapy

Strongest evidence supports using thiazides

Of all antihypertensive drugs, thiazides have the strongest body of evidence
for reducing morbidity and mortality in hypertension.[9,10]

ALLHAT*, the largest antihypertensive trial ever conducted, showed that thiazidebased therapy is at least as effective as treatment based on an ACE inhibitor or a calcium-channel blocker in reducing the risk of major cardiovascular events and death.[11]

A small benefit of ACE inhibitors over thiazides in older men has been suggested based on a post hoc analysis of ANBP2†; this result requires confirmation because the study was not designed to detect differences in treatment effect between men and women.[12] ANBP2 reinforces that there is no difference in effect on cardiovascular event rates between thiazides and ACE inhibitors.

A discussion of the implications of ALLHAT and ANBP2 for drug choices in hypertension is available on the NPS website.

Limit thiazide doses to hydrochlorothiazide 12.5–25 mg/day or equivalent to minimise electrolyte and metabolic disturbances 

Adverse effects associated with the use of higher thiazide doses during the 1970s and 1980s created the perception that metabolic disturbances are a significant problem with these drugs. At lower thiazide doses, however, metabolic adverse effects are unusual and their clinical significance appears low: while elevated cholesterol and new onset diabetes were slightly more common with thiazides than with either
ACE inhibitors or calcium-channel blockers in ALLHAT, these changes did not lead to a higher rate of cardiovascular events or death in the chlorthalidone group.[11]

In choosing which thiazide diuretic to prescribe, note that most evidence of benefit in hypertension comes from studies involving chlorthalidone or hydrochlorothiazide.[11,13–16] Outcomes studies with bendrofluazide or indapamide are limited.[17,18] However, cardiovascular morbidity and mortality benefits seen in clinical trials are assumed to extend to all thiazide and thiazide-like diuretics.

Electrolyte disturbances are possible with all thiazide and thiazide-like diuretics, particularly in older patients; limit doses to a maximum of hydrochlorothiazide 25 mg or equivalent to minimise the risk of hyponatraemia or hypokalaemia. Indapamide is no less likely than other thiazides to cause electrolyte disturbances. ADRAC has most commonly received reports of hyponatraemia with indapamide
2.5 mg[19,20] as opposed to the low-dose, sustained-release indapamide formulation; further post-marketing surveillance is required to determine whether the sustainedrelease preparation causes fewer electrolyte disturbances.

^{*Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial †Second Australian National Blood Pressure study}

People with diabetes should receive early and active blood pressure control

Tight blood pressure control reduces risk of complications

Tight blood pressure control produces a greater reduction in both macroand microvascular disease in diabetes than does intensive blood glucose control.[21]

In people without nephropathy, initiate with a thiazide, an ACE inhibitor, or a beta-blocker

Thiazides, ACE inhibitors and beta-blockers all reduce cardiovascular morbidity and mortality in patients with hypertension and diabetes and are suitable first-line agents in people without renal disease.[11,13,21–23]

Subgroup analyses of comparative outcomes trials have not demonstrated any cardiovascular morbidity or mortality advantage of ACE inhibitors over thiazides in people with diabetes.[11,22]

Beta-blockers are also appropriate first-line agents in people with both diabetes and hypertension[21,22] and are particularly indicated in people with a history of recent myocardial infarction. Bear in mind that beta-blockers may predispose some treated diabetics to hypoglycaemia and mask the adrenergic warning signs of hypoglycaemia (tremor and tachycardia).

In people with nephropathy… 

In people with type 1 diabetes and microalbuminuria or proteinuria, ACE inhibitors slow the progression of nephropathy and should be used first-line.[24]

In people with type 2 diabetes and microalbuminuria, both ACE inhibitors and angiotensin II receptor antagonists reduce protein excretion[23,25], but studies demonstrating an effect on long-term decline in renal function in people with early diabetic renal disease are lacking.

In people with type 2 diabetes and overt nephropathy, angiotensin II receptor antagonists may delay progression of renal disease, although these findings rely in part on changes in the surrogate endpoint of serum creatinine concentration.[26,27] The effect of ACE inhibitors on renal outcomes in people with type 2 diabetes and nephropathy has not been studied.

Calcium-channel blockers are second-line in diabetes

Calcium-channel blockers should be reserved for second-line use in people with diabetes and hypertension. There is inconsistent evidence of a benefit of using calcium-channel blockers in diabetes. Some comparative trials have suggested that dihydropyridine calcium-channel blockers are associated with a higher risk of major vascular events than ACE inhibitors in diabetes.[28,29] In the diabetic subgroup of ALLHAT, however, amlodipine and lisinopril were associated with similar coronary event rates to chlorthalidone.[11]

When selecting an antihypertensive drug, consider potential favourable effects on co-existing conditions

Choose antihypertensive therapy based on compelling indications

Some antihypertensive drug classes should be favoured for initiation in certain patient groups because they have evidence of benefit in particular co-existing conditions. For example, beta-blockers and ACE inhibitors are particularly indicated after acute myocardial infarction and calcium-channel blockers and thiazides are suitable in isolated systolic hypertension.

A complete table of compelling indications is available in Therapeutic Guidelines: Cardiovascular, Version 4 (available from Therapeutic Guidelines Pty Ltd).

Where there is no compelling indication for another class, initiate with a thiazide, unless contra-indicated.

Expert reviewer

Associate Professor Karen Duggan, National Blood Pressure Advisory Committee, National Heart Foundation of Australia

References

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