High blood pressure is recognised as a major and global problem, far in excess of the global burden of disease caused by smoking, unsafe water and poor diet.1 Evidence clearly demonstrates a dose-response relationship between increasing blood pressure and the increasing risk from stroke and coronary heart disease (CHD).2 Importantly, evidence is equally strong that the treatment of hypertension results in a 30% to 35% reduction in strokes and a 20% reduction in heart attacks.3 A reduction in the latter also reduces the global complications also associated with hypertension, such as heart failure and arrhythmias, including atrial fibrillation and ventricular arrhythmias. It is therefore crucial to detect, treat and control high blood pressure, and inadequate or inappropriate treatment of hypertension should be regarded as negligent.
It is therefore no longer a question of whether to treat hypertension, but more a question of who should be treated and how it should be treated. The last few years have provided more insights and some answers to the latter two questions.
Who to Treat?
Hypertension can be defined pragmatically as that level of blood pressure above which the use of antihypertensive treatment provides more benefit than harm.
It is increasingly recognised that hypertensive patients are not an homogeneous population and hypertension per se is not a condition that can be regarded in isolation. All major hypertension management guidelines increasingly recommend the use of risk stratification when approaching the treatment of hypertension. Thus, the approach to the treatment of hypertension has changed somewhat in that it should no longer be treated as an individual disease, but in the context of a patient’s total cardiovascular risk.4,5 Other risk factors, such as diabetes mellitus, hyperlipidaemia, smoking, age and gender, need to be taken into account. Each of these risk factors is cumulative to the overall cardiovascular risk burden and, in managing the hypertensive patient, all risk factors must be managed in an holistic manner, in a ‘package of care’ that includes treating high-risk groups with nonpharmacological and pharmacological measures.
How to Treat?
Many different classes of antihypertensive drugs exist. As hypertension is a huge problem globally, pharmaceutical companies have seen a massive economic market in the development, marketing and promotion of new agents. Until recently, thiazide diuretics and beta-blockers have been regarded as the mainstay of hypertension treatment. Whilst they both have their shortcomings, the fact that they have been tried and tested by time, with large outcome trials, these agents have been advocated as first-line drugs in many previous guidelines.
The scene has now changed. There is an increasing recognition that beta-blockers are ineffective as firstline agents in the elderly and in Afro-Caribbean patients, partly due to the low renin state in these patients. Certainly, the evidence as to whether betablockers are even effective in reducing end-points in hypertension, especially in the elderly, have been extensively debated,6,7 On the other hand, thiazides are inexpensive and effective agents, but clinicians need to be aware that the lowest possible dose should be used, as there is no dose-response antihypertensive effect, whilst higher doses of thiazides are associated with increasing metabolic effects.8
Many randomised controlled trials have also compared the newer agents, such as the alpha-blockers, calcium antagonists, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor antagonists to the thiazides and beta-blockers. The largest of these was the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) in ‘highrisk’ hypertensive patients who were initially randomised to a diuretic (chlorthalidone) versus each of three ‘alternative’ (newer) antihypertensive drugs: an alpha-adrenergic blocker (doxazosin), an ACEinhibitor (lisinopril) and a calcium channel blocker (amlodipine).9 The doxazosin arm10 was stopped early due to an apparent excess of cardiovascular events, especially heart failure, and the data for the remaining arms of the study were recently published showing that the incidence of the primary end-points of fatal CHD and non-fatal myocardial infarction (MI) was essentially identical for thiazide diuretic, an ACE inhibitor and dihydropyridine calcium antagonist arms of the study. Nonetheless, the Afro-Caribbean patients did less well with lisinopril compared with chlorthalidone, with an excess of strokes and cardiovascular events, in keeping with the relative inefficacy of the ACE inhibitors in this ethnic group.
The second mega-trial, the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), which is a trial comparing ‘old combination drugs’ (thiazides (betablockers)) with ‘new combination drugs’ (amlodipine (perindopril)) is on-going, although the lipid-lowering arm data has been recently published.11 Another important recent trial, the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study compared the beta-blocker atenolol with the angiotensin receptor antagonist losartan and found a significant reduction in the primary end-point of cardiovascular morbidity and mortality, as well as a greater reduction in electrocardiogram left ventricular hypertrophy (LVH) with losartan, despite a similar mean blood pressure reduction in both treatment groups.12 Furthermore, the atenolol arm was associated with a higher incidence of newly diagnosed diabetics. Losartan was also shown to be effective in diabetics and in patients with atrial fibrillation, as well as in LVH regression.
Recent insights into the value of lipid-lowering therapy in hypertension are provided by the Medical Research Council (MRC)/British Heart Foundation (BHF) Heart Protection Study (HPS),13 which studied ‘high-risk’ patients with a substantial fiveyear risk of death due to CHD. In this trial, the use of simvastatin at 40mg per day was associated with a significantly lower all-cause mortality (12.9% versus placebo, 14.7%), which was mainly due to a highly significant lower coronary mortality rate. There were also significant decreases in non-fatal myocardial infarctions, fatal or non-fatal strokes and coronary or non-coronary revascularisations. Of the total 20,536 patients that were enrolled, 8,456 (41%) were hypertensive. Subgroup analyses of the hypertensive population also revealed significant benefits from simvastatin at 40mg daily over placebo.
The data from the HPS was complemented by the recent publication of the lipid-lowering arm data from the ASCOT study. In the latter, which studied hypertensive patients at modest risk of cardiovascular disease, atorvastatin 10mg daily was associated with a highly significant reduction in the primary end-point of fatal MI and non-fatal CHD events (by 36%), together with significant reductions in the secondary end-points of stroke (by 27%), all cardiovascular events and procedures (by 21%) and total coronary events (by 29%). Risk reductions in CHD events were unrelated to baseline cholesterol levels and were consistent across the whole range of cholesterol.
Implications for management
The new insights discussed in this article raise the possibility that beta-blockers should perhaps not be used as first-line mono-therapy. They are also less effective in Afro-Caribbean individuals and in the elderly – and many patients with hypertension are elderly. New hypertension management guidelines may soon reflect this reduction in emphasis on betablockers, although it is recognised that these agents do have some value in patients with concomitant coronary artery disease and in the management of cardiac arrhythmias and heart failure due to left ventricular systolic dysfunction.
The data from ALLHAT also advises some degree of caution with the use of alpha-blockers in hypertensives at risk of heart failure. ALLHAT and other trials also confirm the need for combination therapy to achieve adequate blood pressure control – generally <140/85mm of mercury (Hg) in nondiabetics and <130/80mm Hg in diabetics – and, on average, half of all hypertensives will require two or more drugs, while a third will require three or more drugs to achieve adequate blood pressure control. It is likely that the increasing use of combination therapy preparations will be seen, which may go some way in improving drug compliance in patients who are on multiple-drug therapies.
Furthermore, trials such as the HPS and ASCOT have proven the value of an holistic approach to cardiovascular risk management in hypertensive patients with additional risk factors, by the addition of statin therapy, irrespective of serum cholesterol level. The possibility of combination drugs that include an antihypertensive agent plus a statin seems a logical course of action as part of the comprehensive cardiovascular risk management of such patients.
- M Ezzati, A D Lopez, A Rodgers, S van der Hoorn and C J Murray, Selected Major Risk Factors and Global and Regional Burden of Disease, Lancet, 360 (2002) 9,343, pp. 1,347–1,360.
- S MacMahon, R Peto, J Cutler, R Collins, P Sorlie, J Neaton, R Abbott, et al., Blood Pressure Stroke and Coronary Heart Disease: Part I, Prolonged Differences in Blood Pressure: Prospective Observational Studies Corrected for Regression Dilution Bias, ibid., 335 (1990), pp. 765–774.
- R Collins, R Peto, S MacMahon, P Herbert, N H Fiebach, A E Kimberley, J Godwin, et al., Blood Pressure Stroke and Coronary Heart Disease: Part 2, Short-term Reductions in Blood Pressure: Overview of Randomised Drug Trials in Their Epidemological Context, ibid., pp. 827–838.
- World Health Organization, International Society Guidelines for the Management of Hypertension: Guidelines Subcommittee, J. Hypertens., 17 (1999), pp. 151–183.
- L E Ramsey, B Williams, G D Johnston, G A MacGregor, L Poston, N R Poulter and G Russell, Guidelines for Management of Hypertension: Report of the Third Working Party of the British Hypertension Society, J. Hum. Hypertens., 13 (1999), pp. 569–592.
- D G Beevers, Beta-blockers for Hypertension: Time to Call a Halt, ibid., 12 (1998) 12, pp. 807–810.
- E Grossman and F H Messerli, Why Beta-blockers are not Cardioprotective in Elderly Patients with Hypertension, Curr. Cardiol. Rep., 4 (2002) 6, pp. 468–473.
- D G Beevers and R E Ferner, Why are Thiazide Diuretics Declining in Popularity?, J. Hum. Hypertens., 15 (2001), pp. 287–289.
- ALLHAT Officers and Coordinators for the ALLHAT Collaborative Group, Major Outcomes in High-risk Hypertensive Patients Randomized to Angiotensin-converting Enzyme Inhibitor or Calcium Channel Blocker vs Diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) JAMA, 288 (2002), pp. 2,981–2,997.
- Idem., Major Cardiovascular Events in Hypertensive Patients Randomized to Doxazosin vs Chlorthalidone: The Antihypertensive and Lipid-lowering Treatment to Prevent Heart Attack Trial (ALLHAT), ibid., 283 (2000), pp. 1,967–1,975.
- P S Sever, B Dahlof, N R Poulter, et al., Prevention of Coronary and Stroke Events with Atorvastatin in Hypertensive Patients who have Average or Lower-than-average Cholesterol Concentrations in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): A Multicentre Randomised Controlled Trial, Lancet, 361 (2003) 9,364, pp. 1,149–1,158.
- B Dahlof, R B Devereux, S E Kjeldsen, S Julius, D G Beevers, U Faire, et al., Cardiovascular Morbidity and Mortality in the Losartan Intervention for Endpoint Reduction in Hypertension Study (LIFE): A Randomised Trial Against Atenolol, ibid., 359 (2002) 9,311, pp. 995–1,003.
- MRC/BHF Heart Protection Study of Cholesterol Lowering with Simvastatin in 20,536 High-risk Individuals: A Randomised Placebo-controlled Trial, ibid., 360 (2002), pp. 7–22.