What is the first-line antihypertensive for African American

There are well-described ethnic variations in the incidence, pathophysiology and management of hypertensive disease, particularly pertaining to the Black or Afro-Caribbean populations in Africa, North America, the Caribbean and in Europe. Our understanding of the underlying pathophysiology of hypertensive disease and the optimal treatment of hypertension in Black patients continues to evolve, especially with the introduction of new antihypertensive agents, such as the angiotensin receptor antagonists, and the need for prognostic data in this ethnic population. Nevertheless, it has been our perception that there continues to be some uncertainty over the optimal management of such patients. Indeed, the lack of large, long-term prospective randomized trials with hard outcome data has made it difficult to ascertain the precise benefits for the different antihypertensive agents in Black patients. There is also the difficulty of defining a `pure' Black (or White) population, as many subgroups within a particular ethnic group may exist.

This article reviews the management of hypertensive disease in the black population, emphasizing race-related differences in the pathophysiology of hypertension and the importance of tailored management in this group of patients.

Incidence and complications

Hypertension is known to occur more frequently in the black population and is associated with a higher incidence of cerebrovascular and renal complications. For example, strokes are more common in Black hypertensives,1 and hypertension associated end-stage renal failure occurs up to 20 times more commonly in Black patients, compared to non-Blacks.2 In addition, there is a greater tendency to develop left ventricular hypertrophy (LVH); Black patients with mild hypertension have a two-fold higher prevalence of LVH when compared to non-Blacks with comparable blood pressure levels.3

Despite an increased prevalence of both hypertension and diabetes,4 the overall risk of coronary artery disease in the Black male population, in Europe, in the Caribbean and to a lesser extent in North America, is lower than in White males.5 By contrast, Indo-Asians have an excess prevalence of coronary artery disease. This contrast may be due to a multitude of reasons, although many of the traditional risk factors do not fully explain the ethnic differences in cardiovascular disease and stroke. One reason however may be the more favourable lipid profiles, seen particularly in Black males, with higher high-density-lipoprotein (HDL) cholesterol levels and lower plasma triglycerides.5

The increased frequency of cerebrovascular disease, renal complications and cardiac hypertrophy in Black patients may be related to a higher incidence of severe hypertension, including malignant hypertension. The West Birmingham Malignant Hypertension Register, for example, revealed that there was an excess of Black patients with malignant hypertension, who also had higher blood pressures and more severe renal impairment at presentation; such patients had a poorer overall median survival and an increased rate of progression to dialysis.6 Thus, Black patients with malignant hypertension did not do worse simply because they were Black, but they appeared to have poorer blood pressure control and more complications, such as renal damage.

Pathophysiology

Environmental factors are likely to have some influence on the development of hypertension in the Black population. For example, the Kenyan Luo migration study demonstrated that blood pressures in Black rural Africans who migrated to urban areas was significantly increased with greater duration of urbanization, and this appeared to be associated with increases in weight and disturbances of urinary electrolyte balance.7 The whole population blood pressure curve was in fact shifted to the right, corresponding to an increase in mean population blood pressure levels.

Importantly, there are some general differences in the pathophysiology of hypertension between the Black and White populations. For example, Black hypertensives exhibit enhanced sodium retention with a higher incidence of salt-sensitive hypertension, expanded plasma volume and a higher prevalence of low plasma renin activity.8 Reduced sodium-potassium ATPase activity is also associated with hypertension in Black patients, with a tendency towards increased intracellular sodium and calcium concentrations.9 In addition, proteinuria has been observed more frequently in African-Americans, when compared to White patients with similar creatinine levels.10

One explanation for the higher serum creatinine levels, increased protein excretion and the increased incidence of end-stage renal failure in black hypertensive patients may, in part, be related to underlying ethnic differences in renal physiology. When salt-sensitive patients are challenged with a high sodium intake, the blood pressure rises to a greater degree than in the salt-resistant state; whilst the glomerular filtration rate remains the same, renal blood flow rises in the salt-resistant patients and falls in the salt-sensitive group. It has therefore been suggested that this rise in filtration fraction and intraglomerular pressure during high sodium intake might, in part, explain the increased incidence of renal complications, particularly in salt-sensitive black hypertensive patients.11

An additional hypothesis has linked salt sensitivity and insulin resistance, as preliminary data suggests that plasma glucose levels and insulin concentrations are higher in patients with salt sensitivity.12 It is therefore possible that salt sensitivity may exacerbate renal disease by aggravating glucose intolerance and insulin resistance.

Non-pharmacological management

Lifestyle and non-pharmacological interventions in Black hypertensives may result in a significant blood pressure fall, thereby avoiding the need for antihypertensive therapy or leading to a reduction in the number of antihypertensive agents required to achieve optimal blood pressure control.

Sodium restriction

The potential benefits of sodium restriction have been examined in many epidemiological studies, population studies and clinical intervention trials. For example, there is evidence that sodium restriction is beneficial in the management of mild to moderate hypertension,13,14 and that the effects are equivalent to those of low-dose thiazide diuretics.15 In view of the tendency for `sodium sensitivity' in Black hypertensives, moderate sodium restriction, reducing sodium intake to <100 mmol daily, should be considered. In addition, clinical trials suggest that a high potassium intake exerts an antihypertensive effect16 and in view of the fact that Black hypertensives generally have a low potassium intake,17 an increase in the daily dietary intake of potassium to 100–120 mmol daily may be valuable. This is illustrated by a recent American study, where a reduction in dietary sodium (Na) and an increase in dietary potassium (K), thereby decreasing the urinary Na : K ratio, was particularly beneficial in Blacks of lower socioeconomic status.18

Weight control

There is a well-recognized association between hypertension and obesity, and there is a higher prevalence of obesity in black hypertensives, with a mean weight of approximately 20–25% above the desired level.19 Dietary modifications, including weight loss, have been shown to reduce blood pressure,20 and although the weight-loss-related blood pressure fall in Black hypertensives may be less pronounced than in White hypertensives,21 weight control should be positively encouraged.

Alcohol

Chronic moderate alcohol ingestion (three to five drinks daily) is associated with higher blood pressure levels in Black and White patients,22 and advice regarding alcohol moderation is appropriate in all hypertensive patients.

Exercise

Regular isotonic exercise has, in the short term, been shown to reduce blood pressure in hypertensive patients23 and may also have positive effects on weight control. Although data from large long-term comparative studies is not available, regular physical activity should be recommended for hypertensive patients, whatever their ethnic origin.

Pharmacological management

It should be emphasized that severe hypertension is more common in Blacks, but irrespective of ethnic group, early and effective management is needed. Nevertheless, there are some ethnic differences in drug treatment which the clinician should be aware of.

Diuretics

Low-dose thiazide diuretics are probably the first-line treatment in most Black hypertensives. There is evidence that equivalent diuretic doses result in a greater blood pressure fall in Black hypertensive patients, when compared with White controls.24 These enhanced therapeutic effects are likely to be related to the increased `salt sensitivity', low renin activity, reduced Na+K+-ATPase activity and relative expansion of plasma volume. Nevertheless, there has been concern regarding the adverse metabolic effects of diuretics, including hypokalaemia and resultant ventricular ectopy,25 although these are rarely of clinical significance with low-dose diuretic therapy. Diuretics do, however, exert some adverse effects on the lipid profile and glycaemic control, and although the effects are usually not of any great significance, this should be taken into consideration in patients with hyperlipidaemia and diabetes.

Beta-blockers

Beta-blockers reduce blood pressure by attenuating sympathetic effects on the heart, in addition to adrenergic nerve-mediated renin release from the juxta-glomerular apparatus. Beta-blockers are generally less effective in Black hypertensives26 as a result of the tendency towards a low-renin state and a lower cardiac output, with increased peripheral resistance. Higher doses of beta-blockers are therefore required to achieve target blood pressures in such patients,27,28 although the combined alpha and beta-receptor blocker labetalol appears to be equally effective in both Blacks and Whites.29 Younger Black patients may be more responsive than the elderly, as a result of their tendency towards normal renin levels. The differential effects of beta-blockers in Blacks, compared to Whites, is eliminated by the addition of a diuretic.30

Unless there are clear indications, for example in patients following a myocardial infarction, beta-blockers are generally not considered to be first-line monotherapy in Black patients.

Angiotensin-converting enzyme (ACE) inhibitors

ACE inhibitors also demonstrate a less favourable antihypertensive response when used alone in Black patients,31 although this is eliminated by the addition of a diuretic.32 This reduced efficacy results from the low-renin salt-sensitive profile33 and is a particular problem in the elderly Black hypertensive. A comparison of the antihypertensive response between Black and White patients suggests that Black patients require between two and four times the dose of ACE inhibitor to achieve a response similar to that observed in non-Black patients.34

However, numerous studies have demonstrated the beneficial effects of ACE inhibitors in diabetic nephropathy, particularly in the presence of proteinuria,35,36 and these remain first-line anti-hypertensive agents in this group of patients, irrespective of ethnic origin. Indeed, the use of ACE inhibitors has been advocated in non-diabetic Black patients with renal disease,37 in view of their potential beneficial effects on angiotensin II, although further studies are awaited.

Importantly, the potentially life-threatening complication of ACE-inhibitor-induced angioedema is more common in Black patients, with an adjusted relative risk of 4.5 in African-Americans.38 A plausible mechanism for this adverse effect involves the vasoactive peptide bradykinin, and the increased risk in Black patients may occur as a result of racial differences in the kallikrein-kinin system, with increased sensitivity to bradykinin.39 Angioedema normally occurs within the first few weeks of therapy, and patients should be advised to report urticarial symptoms, and to stop the ACE inhibitor immediately in the event of swelling of the lips, face or tongue. A degree of supervision is therefore prudent, and it would be unjustified to withhold ACE inhibitors simply because of the (low) risk of angioedema.

Calcium channel-blockers

Calcium channel blockers are highly effective antihypertensive agents in black patients.40,41 A comparison of the antihypertensive effects of verapamil, atenolol and captopril in hypertensive Black patients demonstrated that verapamil was the superior agent in terms of blood pressure reduction.40 The efficacy of other calcium channel blockers in Black hypertensives has been confirmed including diltiazem,42 nifedipine43 and isradipine, which has been shown to lower blood pressure and significantly reduce left ventricular mass in Black patients.44

The hypotensive response to these drugs is enhanced by a low-renin state45 and a high dietary salt intake,46 features which are generally common in the Black hypertensive population. In the early stages of treatment, calcium-channel blockers may also have a mild diuretic effect, which is related to a reduction in vascular resistance and improvement in renal blood flow.47 Finally, calcium-channel blockers antagonize the vasoconstrictor effects of angiotensin-II,48 with potentially beneficial effects on the progression of renal disease.49 For example, verapamil led to a greater reduction in proteinuria and resulted in a slower rate of decline in creatinine clearance, when compared to atenolol, in Black patients with diabetic renal disease.50

Alpha-blockers

Alpha-receptor-blocking agents reduce peripheral vascular resistance and therefore reduce blood pressure in Black hypertensives. However, the antihypertensive efficacy can be rather inconsistent, because these agents do not address the problems of expanded plasma volume in such patients, and the addition of a diuretic is often required.51 Alpha-blockers are not associated with metabolic abnormalities and have no significant influence on lipid levels or glycaemic control, which would be advantageous in Black hypertensives with hyperlipidaemia or diabetes.

Angiotensin receptor antagonists

The new angiotensin II (AT1) receptor antagonists have been demonstrated to be effective antihypertensive agents, in the general population. Many agents of this class have already been introduced in the UK, such as losartan, valsartan, irbesartan and candesartan.

However, although experimental studies have shown that AT1 receptor antagonists have beneficial effects on cardiovascular structure, preliminary clinical evidence has suggested that losartan may not be effective in regressing left ventricular hypertrophy (LVH),52 although more recent clinical studies have been more encouraging.53 Other agents, such as valsartan, appear to have some data demonstrating LVH regression, but much of the available data with this class of drugs has been in White Caucasian populations, and the role of these agents in the regression of LVH in Black hypertensives remains unclear. The results of prognostic studies, such as the Losartan Intervention for Endpoint Reduction (LIFE) study, are awaited and may contribute significantly in this area.54 Losartan, in common with the ACE inhibitors, has also been shown to reduce blood pressure and proteinuria in patients with primary glomerular disease,55 and long-term outcome studies using these agents in patients with renal disease, are in progress.

There is limited information, at the present time, concerning the efficacy and tolerability of the angiotensin receptor antagonists in Black patients. On theoretical grounds, this class of drugs should be less effective in Black hypertensives, in view of their low-renin state. However, a recent study of the AT1 receptor antagonist valsartan suggested that it is useful in Black hypertensives,56 although this ethnic group only represented a small proportion of the cohort studied. Angioedema has rarely been reported with these agents57 and this may perhaps prove to be an important advantage in Black patients. Nevertheless, the results of further large long-term controlled trials with this class of drugs, particularly addressing the treatment of Black hypertensives, are awaited.

Recommendations

In view of the high prevalence of `salt sensitivity' in Black hypertensives, advice regarding dietary sodium restriction is important, and should be combined with other non-pharmacological measures including weight control, alcohol moderation and regular exercise.

Low-dose thiazide diuretics remain effective, inexpensive first-line agents in Black patients, as are the calcium-channel blockers. There is an increased prevalence of renal complications in Black hypertensive patients and, while there are no long term comparative data, drugs with vasodilating properties, such as calcium-channel blockers, should be considered in view of their possible reno-protective effects.

ACE inhibitors and beta blockers are less effective when used as monotherapy in Black hypertensives, especially when used at low doses, although the combination of either of these drugs with a diuretic eliminates some of the ethnic differences between Blacks and non-Blacks. ACE inhibitors have beneficial effects in diabetic nephropathy, and should be considered in patients with hypertension and co-existent diabetes. Although combined therapy with ACE inhibitors and calcium antagonists, provides some theoretical advantages in patients with renal insufficiency, more clinical data are needed. The newer angiotensin II receptor antagonists have encouraging reported results, but more information is required regarding the efficacy and tolerability of these agents in Black hypertensive patients.

In view of the high prevalence of hypertension in the Black population and the significant incidence of associated complications, effective screening and tailored antihypertensive management, both non-pharmacological and pharmacological, should be employed to address the high morbidity and mortality rates in this important patient group.

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