HYPERTENSION

What is hypertension?

Hypertension, or high blood pressure, is often called the silent killer, because most people with hypertension feel well and have no symptoms. During each heart beat, there is a fluctuation in the pressure exerted on the inside of the arteries. The normal maximum (systolic) pressure is between 110-140mm mercury (Hg) and the minimum (diastolic) pressure is 70-90mm. There is much individual variation in blood pressure, depending on time of day, activity, age, general condition of health, etc, but a consistent reading of greater than 140 for systolic pressure and/or 90 for diastolic pressure is now considered to indicate hypertension, irrespective of age.

Hypertension is classified as being either essential or secondary. Hypertension is said to be essential if no specific cause can be found for it. Essential hypertension accounts for more than 90 per cent of cases. If untreated, it much increases the risk of stroke, heart attack, heart failure, kidney problems, diabetes, etc (see Atherosclerosis, Congestive Heart Failure, Diabetes). Secondary hypertension follows from an underlying disease which may need separate treatment, e.g. kidney disease or hormonal disorders. Hypertension in the circulation through the lung (pulmonary arterial hypertension) is seen in chronic obstructive pulmonary disease (COPD) and has a poor prognosis if untreated.

Who does hypertension affect and what does it cost?

The Health Survey for England has found that about 50 per cent of people aged over 55 have high blood pressure (Figure 1). For adults as a whole, 32 per cent of men and 30 per cent of women have hypertension. Strikingly, in the age range 65-74, about 17 per cent of men and 20 per cent of women are being treated for hypertension but still have a blood pressure above the normal range, and about 30 per cent of both men and women in this age group have hypertension, but are not being treated for it. Amongst those aged 75 or more, 54 per cent of men and almost 63 per cent of women had hypertension that was either untreated or insufficiently treated. Hypertension is a main risk factor for cardiovascular disease of all kinds (stroke, heart attack, angina, etc), which the British Heart Foundation has estimated cost the UK healthcare system around £14.75 billion in 2003, with costs of hospital care accounting for about three quarters of the total. Control of hypertension is therefore a major economic imperative, as well as a medical one.

Present treatments and shortcomings

Antihypertensive medicines fall into eight main classes. Each has strengths, weaknesses and specific applications, and it is not possible to do more here than list the main classes. Following a NICE review, the medicines currently recommended for initial treatment are:

• angiotensin converting enzyme (ACE) inhibitors - they prevent the formation of angiotensin 2 (A-2), a powerful substance that causes narrowing of blood vessels (vasoconstriction) that raises blood pressure
• angiotensin 2 receptor blockers (ARBs) - stop A-2 binding to its receptor site and are recommended if ACE inhibitors are not tolerated
• diuretics - these act by dilating arterial vessels and increasing sodium excretion and urine output, which lowers blood volume and pressure
• calcium antagonists - these inhibit calcium movement into smooth muscles in the walls of blood vessels and the heart, causing muscle relaxation.

No longer recommended for initial treatment, because some evidence suggests that they may lower blood pressure less well than the medicines above and are associated with a raised risk of developing diabetes are beta-blockers, which are classified into those that are heart-selective, those that are non heart-selective, and those that combine beta-blockade with dilating blood vessels. Beta-blockers slow the heart rate and decrease blood output. They are still of value in the management of heart failure and for those who, for example, do not tolerate ACE inhibitors.

Three other types of antihypertensive medicines are used less frequently:

• alpha₁ antagonists block nerve impulses that trigger blood vessel constriction
• imidazoline agonists act on receptors in the brain
• central alpha agonists also act in the brain.

Side effects can occur with any antihypertensive medicine, but differ according to the type of medication and the individual. A doctor will take account of a person's age and general condition and the medicine may be changed if it is not well tolerated.

What's in the development pipeline?

Current medicines can give satisfactory control of blood pressure in many cases, although it may be necessary to use more than one at once. With over 40 compounds in the first five classes of anti-hypertensives listed above, there is a wide choice. However, surveys show that many patients do not achieve target blood pressure levels with existing therapies, perhaps in part due to the need to take several medicines each day, and research into improved antihypertensive medicines continues, as does the development of combinations of existing medicines and dose forms that are easier to take.

New approaches to treatment are less easy to find in such an intensively studied field, but they are possible. Novartis has an orally active renin inhibitor (Aliskiren) which has shown encouraging antihypertensive efficacy in trials, both on its own and when used in combination with other antihypertensives. Aliskiren acts on the same biological system as ACE inhibitors and ARBs (called the renin-angiotensin-aldosterone or RAS system), but it acts at its starting point - the generation of renin - rather than later in the chain of events that, if not inhibited, leads to blood pressure increase.

Other companies are also developing medicines that act in new ways. Myogen has recently started a Phase 3 study of darusentan, a selective endothelin-A receptor antagonist. Endothelin-A binds to receptors in smooth muscle and causes narrowing of the blood vessels, so inhibiting its action should block this blood pressureraising process. Protherics has a vaccine in Phase 2 study that generates antibodies against angiotensin 2 and thus damps down the RAS system. BioMarin Pharma's oral compound tetrahydrobiopterin, also at Phase 2, stimulates an enzyme to release nitric oxide in the cells lining blood vessels, making surrounding smooth muscle relax and reducing blood pressure. Meanwhile, Solvay is developing daglutril, and sanofi-aventis is developing AVE 7688 (Ilepatril). Both of these compounds have reached Phase 2 trial. Lastly, Speedel has SPP635 in Phase 2 trial that shows prolonged duration of action, which should help ensure 24 hour control of blood pressure.

Development of existing classes of antihypertensive medicines has not stopped. Novartis has Exforge, a once-daily fixed combination of valsartan and amlodipine and Chiesi has developed a fixed dose combination of delapril (an ACE inhibitor) and manidipine (a calcium channel-blocker). Takeda, meanwhile, has TAK-491 and TAK-536, both ARBs, in Phase 2 trial as a possible follow-up to candesartan.

Research is also being devoted to treatments for pulmonary hypertension - a form of secondary hypertension often seen in the advanced stages of chronic obstructive pulmonary disease. The inhaled iloprost (Ventavis, Schering) and the oral bosentan (Tracleer, Actelion) have been the main treatments, but Pfizer has sildenafil (Revatio) available in this indication. Eli Lilly also has its PDE-5 inhibitor tadalafil (Cialis) in Phase 3 trial for pulmonary hypertension. Another new treatment is being developed by Biogen Idec, which has an inhaled form of synthetic vasoactive intestinal peptide (Aviptadil) in Phase 2 trial. Selective endothelin-A inhibitors are being developed by Encysive Pharmaceuticals (sitaxsentan) and GSK/Myogen (ambrisentan), both in Phase 3 trial, while sanofi-aventis has ataciguat (Phase 2), Bayer has BAY 63-2521 (Phase 1) for this indication and EPIX has a 5HT_2Binhibitor (PRX-08066) in Phase 2 trial.

The longer-term future

Hypertension is such an important health problem that research into new treatments will continue to be lively. As well as the development of new medications, research into better ways of using the various classes of antihypertensive medicines is also important, with attention paid to outcomes other than blood pressure control, such as protection of kidney function and prevention of heart attacks and strokes being a key focus. Several very large long-term trials in such areas are underway and the next decade will certainly see continued, significant progress in the management of hypertension.

FOR FURTHER INFORMATION CONTACT:

The British Heart Foundation
14 Fitzhardinge Street
London
W1H 4DH
Phone: 0870 600 6566 (Helpline)
Website: www.bhf.org.uk

The Blood Pressure Association
60 Cranmer Terrace
London
SW17 0QS
Phone: 020 8772 4994
Website: www.bpassoc.org.uk