Data support early use of combination therapy
Hypertension is a major cause of cardiovascular mortality and morbidity. Once diagnosed, management needs to take into account, not only the level of elevated blood pressure (BP), but also the degree of cardiovascular risk and the presence or absence of target organ damage.
A GP who has assessed a patient with a blood pressure issue would have traditionally prescribed a single medication plus lifestyle modifications, weight reduction, alcohol restrictions, exercise and importantly, salt avoidance in the diet. When pharmacotherapy is indicated, a stepped care approach is recommended. The majority of patients will require dual therapy and up to 20 per cent will need triple therapy in order to achieve optimal BP control.
There are established hypertension guidelines from North America, the EU and also from NICE and the British Hypertension Society. The British guidelines recommend Angiotensin Converting Enzyme (ACE) inhibitors, as first-line treatments in most people younger than 55 years of Celtic and European descent. These drugs act by suppressing the Renin-Angiotensin-Aldosterone (RAA) System. An angiotensin-II receptor antagonist (ARB) should be considered if the patient is ACE intolerant. ARBs also suppress the RAA system and produce a similar BP reduction to ACE inhibitors. “Based on clinical trials, a new ARB, azilsartan, is coming on the market, which seems somewhat more effective than other ARBs,” Dr Brendan McAdam, Consultant Cardiologist at Beaumont Hospital, said.
The data now suggest earlier use of combination therapy. This cuts down on the number of GP visits and achieves blood pressure-lowering quicker. “There is now a growing move to use combination therapy,” Dr McAdam said.
It takes at least two or sometimes three drugs to control most people’s blood pressure, according to Dr McAdam. Second-stage therapy would involve an ACE or an ARB in combination with either a calcium channel blocker or a thiazide-type diuretic.
The two sets of therapy frequently used are combinations of an ARB or an ACE inhibitor plus a calcium channel blocker (CCB) such as amlodipine or a thiazide diuretic. Both have been shown to be effective. One large trial showed that the combination of the calcium channel blocker and ACE inhibitor seemed to be marginally more effective and had more long-term beneficial effects on hard cardiovascular endpoints.
“Recently, there have been several studies looking at combination therapies. Calcium channel-blockers are very commonly added with the ACE and ARB medications,” said Dr McAdam. “Combination therapies aim to achieve effective blood pressure-lowering, quickly.” A recent trial in several thousand patients with a combination tablet showed there was a benefit through achieving more rapid blood pressure response.
“The polypill involves two drugs in one tablet. Two companies have three-drug combinations to get people with moderate hypertension under control much quicker,” said Dr McAdam. The dihydropyridine-type CCBs (including amlodipine, lercanidipine and felodipine) reduce BP by relaxing the vascular smooth muscle cells and dilating coronary and peripheral arteries. The ‘rate-limiting’ CCBs (including diltiazem and verapamil) affect the myocardial cells, reducing cardiac output and slowing heart rate, in addition to lowering BP. Calcium channel blockers interfere with movement of calcium ions through cell membranes. These may be good for isolated systolic hypertension. Whenever systolic BP is reduced by 10mmHg, irrespective of which agent is used from these classes, both stroke and coronary events are greatly reduced (Turnbull F et al, Lancet 2003). CCBs appear to confer greater protection against stroke but may be less effective than the other agents in the prevention of new-onset heart failure (Mancia G et al J Hypertension 2009).
Diuretics (thiazides and thiazide like) inhibit the reabsorption of sodium at renal tubule level. Low-dose thiazides have been shown to be particularly effective in patients aged over 80 years old and in black populations, while ACE inhibitors and ARBs appear to confer greater protection against coronary events.
Studies have shown that low-dose thiazide-type diuretics (including bendroflumethiazide, hydrochlorothiazide, chlorthalidone and indapamide) produce maximal or near-maximal effects on BP reduction with no added benefit reported at higher dose levels (Wright JM and Musini VM, 2009). Diuretics, such as spironolactone, which act as aldosterone antagonists, have a role as add-on therapy in resistant hypertension. Care must be taken to monitor potassium, as it can induce hyperkalaemia, especially in the presence of renal dysfunction.
The third stage would involve three agents (an ACE or an ARB plus a calcium channel blocker, plus a thiazide-type diuretic).
Fourth-stage therapy would involve the addition of either further diuretic therapy or an alpha-blocker or a β-blocker. Specialist advice might be sought at this point.
For many years, β-blockers were used in the initial management of hypertension. However, there is conflicting evidence about their role in hypertension when used as monotherapy (Ritter JM. BMJ 2011, Wiysonge CSU et al 2007, Mancia G et al, J Hypertension 2009).
β-blockers may be considered as an option for use as combination therapy, especially in patients with existing CV disease (such as angina pectoris, stable heart failure and prior myocardial infarct) or in those intolerant of other therapeutic options. In people who have co-existing coronary artery disease, ACE inhibitors and ARBs would be used. β-blockers would commonly be used to control anginal symptoms.
By getting blood pressure under control, the heart problems and symptoms of angina improve. β-blockers should not be combined with diuretics in patients with existing metabolic syndrome or diabetes mellitus because of their combined dysmetabolic effects, and they should not be combined with a rate-limiting CCB because of the risk of heart block (Mancia G and Grassi G, Brit Med Bull 2010). Alpha receptor blockers (such as doxazosin) act at the alpha 1 receptor to cause vasodilatation. They may be considered as add-on therapy in resistant hypertension. Once the patient is controlled (BP under 140/90mmHg or under 150/90mmHg for those aged over 80 years) regular review is recommended to ensure maintenance of BP control.
Renal denervation — a new percutaneous catheter-based technique — is a potentially innovative treatment for certain people with severe resistant hypertension that has been difficult to control, despite numerous medications. The procedure has been performed in Galway and Dublin in a small group of patients who are very resistant. From the kidney arteries, it targets the sympathetic nervous system that supplies the kidneys. The data from several centres seem to indicate that it is associated with significant lowering of BP in patients with very severe hypertension, which then reduces the need for medications.
ABPM now a standard measurement tool
Overall, the goals of treatment are similar in the high-risk patients with diabetes, coronary artery disease or chronic kidney disease. The issue that arises is the increased difficulty in treatment in those with advanced renal disease because of their co-morbidities. Ambulatory blood pressure measurement (ABPM), and in recent times home monitoring, are increasingly-used tools.
ABPM is now a standard measurement tool. NICE guidelines have adopted this as an essential part of strategy; 24-hour monitoring is the cornerstone of BP diagnosis and assessment of treatment response. Falsely-elevated BP can be a factor among patients who may experience the ‘white-coat effect’.
If night-time blood pressure — the most important prognostic marker — is elevated, a person is at high risk and needs to be treated. “We now have to make sure that the drugs we prescribe bring blood pressure under control over the 24-hour period,” said Prof Eoin O’Brien, Professor of Molecular Pharmacology at UCD’s Conway Institute.
“Only by giving enough drugs to achieve that will we prevent stroke. If we got control of blood pressure in Ireland, we would prevent 5,000 out of 10,000 strokes every year.”
At least 40 per cent of Irish primary care physicians can provide ABPM. Unusually, it has also been available in Irish pharmacies. Until recently — as a result of previous NICE guidelines, which said it was a research tool — little ABPM was carried out in Britain. NICE has now brought out guidelines recommending that 24-hour blood pressure measurement should be offered to everybody who is suspected of having hypertension.
There are a number of organisational aspects to be considered in order to optimise hypertension control in general practice. Where patients are not followed up intensively or where there is no recall system, patients may miss appointments. Compliance is clearly an issue, experts believe, and there is a need to check that patients are taking medication.