David Levy, MD, FRCP
Preferred treatment: angiotensin blockade
It is universally accepted that angiotensin blockade should be preferentially used in hypertensive diabetic patients. Although the evidence for greater cardiovascular risk reduction compared with other drug groups is not overwhelming, the renoprotective benefits in type 2 diabetes, and reduction in renal end points in both type 1 and type 2 diabetes, are so convincing that where possible any antihypertensive regimen should contain an angiotensin-blocking agent at maximum recommended dose. In practice, only severe hyperkalemia, marked deterioration in renal function on starting treatment and angio-oedema should preclude use of one or other of these agents. Many uncontrolled studies have concluded that both ACE inhibitors and ARBs, especially ARBs, reduce the risk of developing AF.
In the GISSI-AF study (2009), valsartan did not reduce recurrent AF, though there is still hope that ARBs may reduce the risk of AF in high-risk primary prevention patients, for example those with LVH and hypertension, or left atrial enlargement. However, for the time being angiotensin blockade should not be used for either primary or secondary prevention of AF.
ACE-i or ARB?
Until recently a hotly contested question, with most systematic reviews and meta-analyses favouring ACE-i treatment over ARBs for cardiovascular event reduction in high cardiovascular risk subjects, but there are no comparative outcome studies in hypertension. HOPE (2000) established ramipril 10 mg daily as a default medication, in view of a significant reduction in cardiovascular events more than 2 years after the end of the active treatment phase of the study (HOPE-TOO, 2005). The combined results of HOPE and two further ACE-i studies in patients with high cardiovascular risk or previous cardiovascular events (EUROPA, 2003, perindopril; PEACE, 2004, trandolapril) confirmed the widespread cardiovascular benefit, but differences in achieved blood pressure, even though they are small, have continued to present difficulties in interpretation. Definitively, the prospective ONTARGET study (2008) of high-risk patients similar to the HOPE population found no benefit of telmisartan 80 mg daily over ramipril 10 mg daily in prevention of major cardiovascular outcomes . The small additional blood pressure reduction with telmisartan carried no advantage, and was associated with a slightly increased risk of hypotension; ramipril, on the other hand, was slightly less well tolerated (cough and angio-edema).
After the LIFE study (2002), the ARB losartan was favoured for diabetic patients with hypertension and LVH (though the comparator was atenolol with its weaker central antihypertensive effects). A detailed MRI substudy of the ONTARGET study found that ramipril and telmisartan improved left ventricular mass and volume to the same degree; since there was no difference in clinical outcomes between the two drugs, ACE-i and ARB treatment again seem to be equally valuable for this indication. Therefore, for hypertension and cardiovascular event reduction in high-risk patients, they are interchangeable.
ACE inhibitors (Table 11.3)
Captopril, the first ACE-i, was introduced nearly 30 years ago. We are still learning how to use them. Groups with low renin levels (older or black people) tend to have a weaker blood pressure response to an ACE-i (and to beta-blockers) than younger or white people (e.g. in ALLHAT mean SBP was 4 mmHg lower in black patients treated with chlorthalidone compared with lisinopril). Low-sodium diets and diuretics help blood pressure control by increasing renin levels. However, the evidence for worse clinical outcomes is not conclusive, especially in treat-to-target studies. For example, in the important AASK study (2002) African- Americans with established hypertensive renal disease (eGFR 20–65 mL/ min) had fewer hard renal end points with ramipril treatment than with either metoprolol or amlodipine, for a similar reduction in blood pressure . ACE inhibitors should be priority treatment for all ethnic groups with hypertension associated with diabetes, renal impairment or proteinuria.
Cautions and side-effects
Increasing serum creatinine and falling eGFR
These powerful and beneficial drugs need careful use and diligent monitoring. However, continuing concern about precipitating acute kidney injury still prevents angiotensin blockade being started and, equally importantly, discourages titration of doses to maximum therapeutic levels, particularly in those with impaired renal function, the very patients who stand to gain the most benefit. Measure creatinine, electrolytes and eGFR about 1 week after starting treatment (see Box 11.4). For unknown reasons, serum creatinine often increases by up to 30% (this applies to ARBs as well). It is not associated with long-term harm; on the contrary, it markedly reduces renal end points, regardless of the stage of CKD. If the rise is greater than 30%, stop the medication and ask for advice. If there is no change in serum creatinine after the first dosage step, then it is unlikely with further increases. Those at risk of more rapid deterioration can be identified:
- widespread atherosclerotic disease, with an increased risk of bilateral renal artery stenosis;
- high-dose diuretics, often associated with hypotension, for example in heart failure;
- those taking NSAIDs or cyclooxygenase (COX)-2 inhibitors.
Once the need for angiotensin blockade is established, if there is concern about starting treatment, refer for further advice and careful monitoring.
Hyperkalemia (serum K+ ?: 5.6 mmol/L)
Hyperkalemia is a major problem, more troublesome than changes in measurements of renal function, and a small proportion of patients, perhaps 5%, cannot have any angiotensin-blocking treatment because of severe hyperkalemia (K+ > 6.0 mmol/L) on even minimal doses. High serum potassium is common to begin with because of type 4 renal tubular acidosis (hyporeninemic hypoaldosteronism). Angiotensin II stimulates adrenal aldosterone secretion, and both ACE inhibitors and ARBs therefore impair urinary potassium excretion; the risk of hyperkalemia in people with diabetes treated with angiotensin blockade is much higher than in non-diabetic renal disease (Box 11.6).
Cough and angio-edema
ACE-i-induced cough is common, but the data from the literature varies. Most studies quote 5–20%. After stopping the medication, it usually lingers for about 1–4 weeks, occasionally up to 3 months. It seems to be more common in smokers. Rechallenging with another ACE-i is not worthwhile; move to an ARB. Angio-oedema is rare, occurring in about 1 in 500 starting ACE-i treatment. Most cases occur in the first 30 days, but at a constant low rate thereafter up to a year or longer. Smokers, black patients, and people with allergies are more susceptible.
ACE inhibitors and ARBs have been known for many years to be teratogenic when taken during later pregnancy. There is now evidence for increased risk after exposure during early pregnancy. Reliable contraception or alternative blood pressure medication must be used in women of childbearing age.
Angiotensin receptor blockers (Table 11.4)
Losartan was the first ARB, introduced in 1995. Its patent expired in 2009, and other compounds will shortly be available in generic form.
The accumulated evidence (see above and Chapter 8) is that ARBs and ACE inhibitors are entirely comparable in their cardiac and renal benefits, and adverse biochemical effects (hyperkalemia and initial worsening of renal function) are also similar. However, they do not cause cough (though angio-edema can occur rarely). They are all long-acting, and can be taken once daily.
CCBs are the best ‘broad-spectrum’ antihypertensives. They have been around for many years – the prototype dihydropyridine CCB nifedipine was first used in the 1970s; amlodipine, currently the most widely used CCB, in the early 1990s – and their safety and benefits in diabetes have been underplayed (concerns were raised about their safety in the mid-1990s, though they were quickly allayed). The dihydropyridines do not have any antiproteinuric effects (see Chapter 8), but they seem to reduce the burden of carotid and coronary atherosclerosis, perhaps to a greater extent than ACE inhibitors. For example, in the CAMELOT study (2004), cardiac end points in normotensive type 2 patients were significantly reduced by amlodipine 10 mg daily compared with enalapril 20 mg daily, and ultrasound measurements of coronary atheroma tended to be lower .
Dihydropyridine CCBs are especially valuable in the following clinical settings:
- isolated systolic hypertension in elderly people and hypertension in black people;
- where there is associated angina;
- as initial treatment in patients with widespread atheroma while renal artery stenosis is being investigated;
- in suspected secondary causes of hypertension (e.g. Conn’s syndrome, pheochromocytoma) they are safe clinically and do not interfere with diagnostic endocrine chemical tests;
- where rapid reduction in SBP is required (acute or ambulatory setting), especially where there is impaired renal function.
They are metabolically neutral, with possibly a slightly increased risk of precipitating diabetes in the susceptible compared with angiotensin-blocking agents. They are potentiated by low-dose diuretics, and are particularly effective in combination with angiotensin-blocking agents. High-dose dihydropyridines frequently cause symptomatic peripheral oedema and headaches. Gum hypertrophy may occur in up to 40% of nifedipine-treated patients, but it also occurs occasionally with diltiazem, an important caution in diabetes, where gingival disease is already common. Dihydropyridines are safe in combination with beta-blockers, but diltiazem/verapamil and beta-blockade can cause profound bradycardia and heart block. Some guidelines support the use of combination dihydropyridine and non-dihydropyridine CCBs in hypertension, but there is only one published report of the combination, and neither drug was used in maximum doses.
Antiproteinuric effects of diltiazem and verapamil
Dihydropyridines, though effective antihypertensive agents, do not reduce proteinuria, nor reduce progression to renal end points (IDNT; see Chapter 8). Verapamil/diltiazem are often stated to reduce proteinuria by up to 20%, but the data are inconsistent and there are no long- term studies of renal outcomes. Where there is residual proteinuria after maximum angiotensin blockade, starting diltiazem/verapamil and care- fully monitoring proteinuria, or changing a dihydropyridine to diltiazem/verapamil might be of value, especially if there are dihydropyridine side-effects. However, the evidence for antiproteinuric effects of thiazide diuretics and some beta-blockers is more solid.
Prescribing CCBs (Table 11.5)
Apart from nifedipine and felodipine, the dihydropyridines have long half-lives, and are taken once daily. Nifedipine and diltiazem/verapamil are short-acting agents, and must be prescribed as modified-release or long-acting preparations. The British National Formulary recommends prescribing by brand name not generically, because of variable bioavailability between brands. The difficulties are compounded by the wide dose range and multiple doses available, but these are valuable drugs and it is worthwhile taking care initiating and continuing prescriptions.
Beta-blockers (British National Formulary, section 2.4)
Non-selective beta-blockers (e.g. propranolol, timolol) are no longer used in hypertension. The f)1- selective agents (e.g. atenolol, bisoprolol, metoprolol) are still widely used as secondary prevention after myocardial infarction, but often at low doses compared with those recommended for hypertension. Recent clinical trial results have led to cooling of enthusi- asm for beta-blockade in general, despite the similar outcomes compared with captopril in the intensive blood pressure arm of UKPDS. ALLHAT did not contain a beta-blocker arm, and the atenolol/bendroflumethiazide combination in ASCOT-BPLA was less effective in preventing stroke and cardiovascular events than the CCB/ACE-i arm, though there was no difference in the primary outcome, myocardial infarction. Atenolol in particular has weak effects on stroke prevention, but this may reflect the fact that beta-blockers, like angiotensin-blocking agents, are less effective in older people with their lower renin state, and because they have a weaker effect on central (aortic) pressures, a prominent problem in the systolic hypertension resulting from stiff arteries in older people and those with diabetes. They are still effective in younger, obese, hypertensive patients with high adrenergic drive. Although the side-effect profile is apparently poor (fatigue, depressive symptoms, sexual dysfunction), this is not reflected in clinical trials, where subjects were not more likely to discontinue treatment compared with placebo. Nevertheless, these symptoms may be disruptive in individual patients.
The newest (‘third-generation’) beta-blockers, in use since the mid- 1990s, have a better metabolic profile than other agents in the class, and may be preferable in diabetes, though there are no long-term outcome studies.
- Carvedilol, a non-selective beta-blocker, also has vasodilating alpha- blocking effects. Carvedilol 6.25–25 mg b.d. was compared with metoprolol 50–200 mg b.d. in the GEMINI studies, which found that carvedilol improved insulin sensitivity. There was no change in HbA1c, which increased only slightly, and not clinically significantly, by 0.15% with metoprolol . Lipids were slightly better with carvedilol, and fewer patients progressed to microalbuminuria.
- Nebivolol is a highly selective f)1-adrenergic beta-blocker that also vasodilates, but through a direct endothelial effect mediated by nitric oxide. It is given as a fixed dose of 5 mg daily, though 10 mg daily has been used. It also improves measures of central blood pressure, while having similar effects to atenolol on brachial blood pressure.
- Labetalol, a combined beta- and alpha-blocking agent, is no longer used out of pregnancy.
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David Levy, MD, FRCP, Consultant Physician, Gillian Hanson Centre, Whipps Cross University Hospital; Honorary Senior Lecturer
Queen Mary University of London London, UK
This edition first published 2011, © 2011 by David Levy. 1st edition 1998 (Greenwich Medical Media/Cambridge University Press) 2nd edition 2006 (Altman Publications)