The final article in our series on hypertension and its treatment looks at advances in the understanding of the treatment of hypertension. Highlights from the recently updated British Hypertension Society guidelines are also included
Hypertension is a rapidly moving clinical field with frequent developments in new pharmacological agents and management strategies. Perhaps more importantly, there have been substantial advances in our understanding of how best to use the drugs available to us. In the final article of this series, we aim to review some of the more important advances in our understanding of the treatment of hypertension over the past few years.
Patients with a combination of hypertension and diabetes mellitus are at particularly high risk of cardiovascular disease. This risk is more than would be expected from either risk factor alone.1 The insights from the United Kingdom prospective diabetes study (UKPDS), published in 1998, examined two facets of hypertension care in patients with diabetes. First, whether strict blood pressure control might reduce both adverse events and the progression of end-organ damage, and secondly, in view of reports that angiotensin converting enzyme (ACE) inhibitors might be particularly beneficial in diabetic hypertensives, whether the ACE inhibitor captopril was more effective in preventing diabetic complications than the b-blocker atenolol.
The first component of UKPDS found that strict blood pressure control (ie, attaining a mean blood pressure of 144/82mmHg, compared with 154/87mmHg) using either a b-blocker or an ACE inhibitor, produced significant benefits in diabetic patients.
There were significant reductions in any diabetes-related end point, including diabetes-related death or the development of heart failure, microalbuminuria and progression of diabetic retinopathy, in the strict blood pressure control group.2 Indeed, strict blood pressure control was more effective than tight glycaemic control in protecting against vascular endpoints. In the second part of UKPDS, captopril showed no benefit over atenolol in reducing either macrovascular disease, such as myocardial infarction and peripheral vascular disease, or microvascular disease, such as diabetic retinopathy.3 This was despite previous small studies demonstrating an advantage for ACE inhibitors in treating diabetic patients, particularly in reducing proteinuria.4 It, therefore, appears that the benefits for patients with diabetes of ACE inhibitors may simply be a product of blood pressure reduction, which can be attained with any antihypertensive drug. Results from further large studies that are already underway will be required to settle the issue.
The level to which blood pressure should be lowered has been controversial. Patients with treated hypertension remain at higher risk of cardiovascular events than those with normal blood pressure. Some experts have argued that this is because blood pressure levels have not been lowered to that of normotensive patients, while others contend that lowering blood pressure beyond a certain point may be harmful. The latter argument stems from the fear that if the blood pressure of those with pre-existing coronary artery disease were to be reduced too much, myocardial ischaemia and infarction might occur.
The hypertension optimal treatment (HOT) trial, which was published in 1998, set out to answer two questions. First, whether achieving a lower blood pressure target was beneficial and, secondly, whether adding aspirin 75mg to antihypertensive medication would reduce cardiovascular events.
The HOT trial randomised 18,790 patients to three diastolic blood pressure targets of 90, 85 and 80mmHg or less. Unfortunately the separation of blood pressures achieved was less than half that planned and the difference between the groups was therefore not significant. However, there was no evidence of increased mortality among those with the lowest blood pressures. On re-analysing the data, the investigators found that the diastolic blood pressure associated with the lowest risk of major cardiovascular events was 82.6mmHg.
In one subgroup - the diabetic patients - a clear difference in major cardiovascular events was noted between the different target groups, with a 51 per cent reduction in those with a target blood pressure of 80mmHg compared with those with a target of 90mmHg.5 As a result of this finding, combined with that of the strict blood pressure control arm of the UKPDS, the latest World Health Organisation-International Society of Hypertension guidelines now recommend that a blood pressure of <130/85mmHg should be the target in patients with diabetes.6
Although the arterial tree is subjected to increased pressure in hypertensive patients, paradoxically the complications of hypertension (such as myocardial infarction and stroke) are mainly thrombotic rather than haemorrhagic. The HOT investigators therefore examined whether treatment with aspirin would reduce thrombotic events in treated hypertensive patients. Approximately half the patients in the trial were randomised to aspirin 75mg daily and half to placebo. Over a mean follow-up of 3.8 years, there was a statistically significant (15 per cent) reduction in major cardiovascular events in the aspirin group, although there was no reduction in overall or cardiovascular mortality. This was achieved at a cost of 59 additional non-fatal bleeds, mainly gastrointestinal. Thus, for each major cardiovascular event prevented there was approximately one major non-fatal bleed, even among the well-controlled hypertensive patients in the HOT study.5
Overall, the risk-benefit ratio of aspirin was disappointing and the routine addition of aspirin to antihypertensive medication cannot be recommended as primary prevention. Nevertheless, patients who have already suffered a stroke or myocardial infarction have previously been shown to benefit from aspirin as secondary prevention and should, therefore, receive aspirin, whether or not they have hypertension.7
The past few years have seen the introduction of a whole new class of antihypertensive - the angiotensin II antagonists. Although experience with these drugs is limited, they may have the advantage of causing fewer side effects than other antihypertensive drugs.
Another new drug is moxonidine, which is a refinement of the older centrally-acting agents. Other agents are in the drug development pipeline but are unlikely to reach the market for some years.
Angiotensin II receptor antagonists The angiotensin II antagonists act on the renin-angiotensin system. Although their action is similar to the ACE inhibitors, they have important differences and offer advantages, particularly in terms of tolerability. Angiotensin II is the final product of the renin-angiotensin system. It is an octapeptide derived from its inactive precursor - angiotensin I - by the action of ACE.8 Angiotensin II is a significant contributor to the pathogenesis of arterial disease, hypertension, left ventricular hypertrophy, heart failure and renal disease. Whereas ACE inhibitors work by reducing the conversion of angiotensin I to angiotensin II, the angiotensin II antagonists block the action of angiotensin II at its peripheral receptors (see PJ, September 4, p351).
Although ACE inhibitors are successful drugs they have some disadvantages. ACE is not a specific enzyme and is involved in the breakdown of many other substances, such as bradykinin. The use of ACE inhibitors results in increased levels of this substance, giving rise to the common side effect of cough and the less common (but serious) complication of angioedema.9 Furthermore, because ACE inhibitors are competitive inhibitors of ACE, the secondary increase in levels of angiotensin I (due to loss of negative feedback) can overcome the ACE blockade, leading to a return of angiotensin II levels to normal with chronic ACE inhibitor use. It is also probable that there are other non-ACE pathways for the conversion of angiotensin I to angiotensin II, involving chymases and tissue plasminogen activator. For this reason, ACE inhibitors do not comprehensively block the renin-angiotensin system. By acting at the peripheral receptor, angiotensin II antagonists overcome these problems, resulting in significantly fewer side effects.
Angiotensin II antagonists lower blood pressure by decreasing peripheral vascular resistance without affecting heart rate and cardiac output.9 There are currently four agents licensed in the United Kingdom - losartan, irbesartan, valsartan and candesartan, which are all suitable for once daily use. In clinical trials, the angiotensin II antagonists produced reductions in blood pressure equivalent to the ACE inhibitors and other antihypertensive agents. As with the ACE inhibitors, they are somewhat less effective in patients with low levels of renin, such as blacks and the elderly, but their action may be potentiated by the addition of a diuretic.
The main advantage of the angiotensin II antagonists is that they are well tolerated. For example, one study comparing losartan with ACE inhibitors, b-blockers and calcium channel blockers found that the incidence of any drug-related adverse experience, including cough, with losartan was similar to that of placebo. First dose hypotension occurred in only 0.4 per cent of patients with losartan 50mg.10 However, angioedema has been reported with losartan, albeit rarely. It appears that the angiotensin II antagonists may perhaps be an alternative, or even offer further improvements over, ACE inhibitors, in heart failure. A recent trial in elderly patients with heart failure found lower mortality among those treated with losartan compared with those treated with captopril.11 As with ACE inhibitors, there are data to suggest a beneficial effect in reducing proteinuria.8
Moxonidine Centrally acting agents, such as clonidine and methyldopa, which reduce sympathetic outflow by stimulating a2 adrenoceptors in the central nervous system, have been extensively used in the past to treat hypertension. Although effective, they have largely been superseded by newer agents due to their side effects of sedation and dry mouth, as well as the problem of rebound hypertension on withdrawal. Nevertheless, moxonidine represents the first of a new class of centrally-acting antihypertensive drugs - the selective imidazoline receptor agonists. By stimulating central imidazoline receptors, moxonidine also reduces central sympathetic outflow, without the dry mouth and sedation caused by central a2 receptor blockade. Moxonidine also reduces peripheral vascular resistance, without an increase in heart rate, and may also decrease plasma renin activity and, by direct action on the kidney, may increase the excretion of sodium and water.12 In a series of small, controlled studies, moxonidine has been shown to be superior to placebo and comparable to the main classes of antihypertensive drug in lowering blood pressure.13 However, there are no long-term studies with survival or cardiovascular events as endpoints.
In terms of side effects, moxonidine causes fewer problems with dry mouth than clonidine but other side effects, such as sedation, headache, nausea and sleep disturbance, may occur. Overall, moxonidine appears to be as well tolerated as the main classes of antihypertensive drug. Moxonidine has no adverse effects on plasma lipids and glucose. In summary, moxonidine is an effective antihypertensive agent but, although it seems to be an improvement over clonidine, it has not been demonstrated to have major advantages over more established drugs.
Endothelin receptor antagonists Endothelin, a vasoactive peptide discovered in 1988, is one of the most potent vasoconstrictors known. Endothelin is produced in a wide variety of tissues, including the vascular endothelium. Exogenous administration induces hypertension in both man and laboratory animals.14
The search has been on for agents that will block the action of endothelin at one or more of its receptors. Although no compounds are likely to reach the market in the immediate future, progress has been made. For example, the endothelin receptor antagonist bosentan has recently been demonstrated to be effective in a short-term study in essential hypertension.15
Although apparently less exciting than new classes of drugs, the realisation that blood pressure needs to be managed in the context of overall risk is perhaps the most important advance in the past few years. The importance of considering serum cholesterol, although obvious, has been much neglected. Hypertensive patients tend to have higher cholesterol levels than the general population and it is well recognised that those patients with both raised blood pressure and raised cholesterol are at particularly high risk of cardiovascular events.16,17 As long ago as 1987, it was found that treating hypertension alone in patients with raised cholesterol had little impact on cardiovascular events.18
The treatment of hypercholesterolaemia has been transformed by the introduction of the 3-hydroxy-3-methylglutaryl (HMG) coenzyme A reductase inhibitors (statins).The value of statins in primary prevention in patients at high risk of coronary heart disease has been clearly demonstrated.19 Two large trials are now underway, on either side of the Atlantic, to examine the value of a statin in hypertensives with even modestly raised cholesterol levels.
Dr Spencer is a research fellow and Dr Lip is consultant cardiologist and reader in medicine at the University department of medicine, City hospital, Birmingham
Since this series of articles was originally written, the expected new guidelines on hypertension management from the British Hypertension Society have been published, both in summary (British Medical Journal 1999;319:630) and in full (Journal of Human Hypertension 1999;13:569). The opinions expressed in this series largely concurred with those of the new guidelines, the main features of which are outlined below: