Historically, data from a number of large trials support the overall conclusion that antihypertensive therapy with diuretics and β-blockers has a major beneficial effect on a broad spectrum of cardiovascular outcomes. Similar placebo-controlled data pertaining to the newer agents are generally lacking, except for stroke reduction with the calcium channel blocker nitrendipine in the Systolic Hypertension in Europe trial. However, there is substantial evidence that ACE inhibitors, and to a lesser extent ARBs, reduce adverse cardiovascular outcomes in other related populations (eg, patients with diabetic nephropathy, heart failure, or postmyocardial infarction and individuals at high risk for cardiovascular events). Most large clinical trials that have compared outcomes in relatively unselected patients have failed to show a difference between newer agents - such as ACE inhibitors, calcium channel blockers, and ARBs - and the older diuretics and β-blockers with regard to survival, myocardial infarction, and stroke. Therefore, experts recommend diuretics as the first-line treatment of most older patients with hypertension because these agents are less expensive than the newer agents. Exceptions are appropriate for individuals who have specific indications for another class of agent, such as postmyocardial infarction patients (β-blockers, ACE inhibitors), patients with diabetic nephropathy (ACE inhibitors, ARBs), or other comorbid conditions.

Table 11-4 provides suggestions for individualizing first-line treatment based on compelling indications.

More recently, the perception that all antihypertensive drugs are equally effective at controlling cardiovascular risk has been challenged by the results of the ASCOT trial, which suggest that more modern agents (amlodipine/perindopril) are superior to the older combination (atenolol/bendroflumethiazide). For the reasons discussed above, many experts would suggest that β-blockers no longer be considered ideal first-line drugs in the treatment of hypertension without compelling indications for their use and would tend to restrict the use of thiazide diuretics to older patients in whom they are particularly effective, The predominant use of thiazides in older patients would also limit exposure to the cumulative metabolic consequences of these drugs, a particular concern in young persons with hypertension who are subject to lifelong therapy.

For the purpose of devising an optimal treatment regimen, drugs can be divided into two complementary groups easily remembered as AB and CD. A and B refer to drugs that interrupt the renin-angiotensin system (ACE /ARB and β-blockers) and C and D refer to those that do not (calcium channel blockers and thiazide diuretics). Combinations of drugs between these groups are likely to be more potent in lowering blood pressure than combinations within a group. Drugs A/B are more effective in young, white persons, in whom renins tend to be higher, and drugs C/D are more effective in old or black persons, in whom renin levels are generally lower. It is also important to note that antihypertensive treatment is effective at reducing cardiovascular risk at all ages, including the very elderly.

Figure 11-3 illustrates guidelines established by the BHS for developing a rational antihypertensive regimen. In these guidelines, “B” is placed in parentheses. This reflects the increasingly prevalent view that β-blockers should no longer be considered an ideal first-line agent. In trials that include patients with systolic hypertension, most patients require two or more medications and even then a substantial proportion of patients does not achieve the goal systolic blood pressure of < 140 mm Hg (< 130 mm Hg in high-risk individuals). In diabetic patients, three or four drugs are usually required to reduce systolic blood pressure to < 140 mm Hg. In many patients, blood pressure cannot be maintained at the recommended goal of < 130 mm Hg with any combination. As a result, debating the appropriate first-line agent is less relevant than determining the most appropriate combinations of agents. This has led many experts and practitioners to reconsider the use of fixed-dose combination antihypertensive agents as first-line therapy in patients with substantially elevated systolic pressures (> 160 mm Hg) or difficult-to-control hypertension (associated diabetes or renal dysfunction). Based both on antihypertensive efficacy and complementarity, combinations of a diuretic and an ACE inhibitor (or an ARB if patient is intolerant of ACE inhibitor) or a diuretic and a β-blocker are recommended. In younger white patients, the best choice is probably a combination of an ACE inhibitor and a calcium channel blocker. The initial use of low-dose combinations allows faster blood pressure reduction without substantially higher intolerance rates and is likely to be better accepted by patients.

When an initial agent is selected, the patient should be informed of common side effects and the need for diligent compliance. Treatment should start at a low dose, and unless the initial blood pressure is very high (> 160/100 mm Hg), follow-up visits should usually be at 4- to 6-week intervals to allow for full medication effects to be established (especially with diuretics) before further titration or adjustment. If, after titration to usual doses, the patient has shown a discernible but incomplete response and a good tolerance of the initial drug, a second medication should be added.

Hypertension can be controlled in most patients with one-drug or two-drug regimens that combine complementary agents. A small number of patients require three, four, or even more medications in combination. Patients who are compliant with their medications and who do not respond to these combinations should usually be evaluated for secondary hypertension before proceeding to more complex regimens.

Figure 11-3 The British Hypertension Society’s recommendations for combining blood pressure lowering drugs. The “ABCD” rule. A = Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker; B = β-blocker (the parentheses indicate that β-blockers should no longer be considered ideal first-line agents); C = calcium channel blockers; D = diuretic (thiazide). (Reproduced with permission from: Guidelines for management of hypertension: report of the Fourth Working Party of the British Hypertension Society, 2004-BHS IV. J Hum Hypertens 2004;18:139-185.)