David Levy, MD, FRCP
Pharmacological treatment: general features
The value of ranking antihypertensive agents
The near-universal adoption of treatment algorithms using strong recommendations for first-, second-and third-line treatments, habitual for the past 30 years or more, has been challenged by the European Society of Hypertension (ESH, 2007, 2009). The logic of their approach is that there are certain general agreements on blood pressure management.
- The major benefit of antihypertensive treatment is lowering of blood pressure itself, not the means by which it is achieved.
- Different classes of agents have only minor differences in cause-specific outcomes, and these are unlikely to be apparent in individual patients, as opposed to large RCT cohorts.
- When used at recommended doses, the various classes of agents have very similar blood pressure-lowering effects.
- The cardiovascular outcomes in an individual patient cannot yet be predicted.
- Relatively few combinations have formal hard-point outcome studies.
- Most patients will require two or more agents to achieve target blood pressure.
- All antihypertensive agents have benefits and side-effects.
Given these, in place of strict rankings, the European guidelines suggest preferred drugs in different specific conditions – not surprisingly, angiotensin blockade in diabetes – but then focus on strategies for combining agents. The contrasting approaches of NICE and ESH are shown in Fig. 11.4, with the high cardiovascular risk strategy, appropriate for many people with diabetes, selected for the ESH example. Most practitioners probably already use a combination of these approaches, but it is reassuring that a wide body of opinion supports a less hierarchical approach to the management of hypertension.
Still a controversial area in primary prevention, but there is no controversy over long-term low-dose aspirin use in secondary prevention patients with evidence of established atherosclerotic disease (myocardial infarction, stroke, coronary interventions, peripheral vascular disease, definite atheroma on coronary angiography, plaque on carotid Doppler scanning).
No single clinical trial has given definitive results, and aspirin is no longer licensed in the UK for primary prevention (for details see www.mhra.gov.uk/drugsafetyupdate, October 2009). In meta-analyses, there are modest reductions in myocardial infarction and stroke, for example relative risk reductions of 9% for coronary heart disease, 15% for stroke. The effects are greater for coronary heart disease in men, and for stroke in women. Against this, there is a slightly increased risk of hemorrhagic (though not fatal) stroke, and around 50% increased risk of gastrointestinal bleeding in those without a history of ulcer disease. The more cardiovascular risk factors, the greater the increased bleeding risk. There is continuing concern about an increase in pharmacological aspirin resistance in people with diabetes, possibly through increased production of non-platelet-derived thromboxane A2 (smoking, hypertension and hyperlipidemia have similar, additional, effects). Recall, however, that apparent aspirin resistance may be caused simply by failure to take the medication: 40% of people with cardiovascular disease are reported not to take aspirin as prescribed.
The 2010 proposals, though based on a relatively weak level of evidence, are as follows:
- Use a clinical risk calculator (e.g. UKPDS risk engine, www.dtu.ox.ac/ riskengine/index/php). Suggest aspirin use in adults with a greater than 10% 10-year cardiovascular disease event risk but who do not have increased risk of gastrointestinal bleeding (no previous bleed or peptic ulcer disease, no concurrent NSAID or warfarin use).
- Use clinical approximation (men over 50 and women over 60). The guideline suggests aspirin treatment if there is one or more additional cardiovascular risk factors (smoking, hypertension, dyslipidemia, family history of premature cardiovascular disease, albuminuria), but as always these simple lists do not distinguish for example between current and past smokers, controlled or uncontrolled hypertension, statin- treated patients, and so on; most type 2 patients will have several of these factors.
- Type 1 diabetes. Very limited data. Patients with retinopathy or microalbuminuria or macroalbuminuria should probably take aspirin because of the significantly increased cardiovascular risk associated with these complications. There is no evidence for increased risk of retinal bleeding with aspirin, though dual antiplatelet therapy should probably not be used in retinopathy patients, especially if there is pre-proliferative or proliferative retinopathy. Patients with completely uncomplicated type 1 diabetes probably do not benefit, though after a very long duration (e.g. 20 years) there may be increased cardiovascular risk even if there is no microalbuminuria and strictly normal lipids. Discuss individually with patients; the decision may require specialist advice.
- Hypertension. The ADA (2004) recommends that hypertensive type 1 and 2 patients over 40 years old or with more than 10 years of known type 2 diabetes who achieve blood pressure below 150/90 mmHg should take low-dose aspirin, which reduces cardiovascular events by about 15% and myocardial infarction by 36%, in addition to the risk reduction of the antihypertensive medication itself.
Metabolic effects of thiazide or thiazide-like diuretics and beta-blockers
Concerns about the effects of thiazides and beta-blockers on glucose metabolism, lipid profiles and the risk of developing diabetes have been magnified to the point at which these valuable agents, especially the thiazides, are often considered forbidden in the management of diabetes. Hypertension in diabetes, especially resistant hypertension, cannot usually be managed without a thiazide or thiazide-like diuretic. It is therefore important to appreciate the magnitude of the effects.
- Combined beta-blocker and thiazide treatment increases both mean fasting glucose and LDL by only about 0.1–0.3 mmol/L (glucose 2–5 mg/dL, LDL 4–12 mg/dL), triglycerides by about 0.2–0.5 mmol/L (18–44 mg/dL), and uric acid by 20%, values similar to those of the variability of the measurement.
- Thiazide and beta-blocker treatment in most RCTs increases the risk of diagnosed diabetes; for example, in the ALLHAT study, the 4-year incidence of new-onset diabetes was 3.5% higher in the chlorthalidone-treated group compared with the lisinopril-treated group (11.6% vs. 8.1%) .
- Beta-blocker glucose effects are larger than those of thiazides. Non-selective beta-blockers, rarely used in long-term treatment now, reduce glucose uptake in muscle by blocking f)2-adrenergic stimulated blood flow, as well as first-phase insulin secretion. However, even selective beta-blockers such as metoprolol, widely used in ischemic heart disease and heart failure, increase HbA1c, though only by about 0.15%. In comparison with the metabolically neutral carvedilol, patients treated with metoprolol required more statin starts and up-titrations in clinical trials. In the individual patient, changes in glucose or lipid medication will be barely discernible. Nevertheless, these agents should be reserved as lower priority treatment in people whose diabetes management might require substantial shifts if they were to be used, especially in combination, for example:
- (a) those with the dysglycemia of the pre-existing metabolic syndrome, who may be precipitated into full-blown diabetes;
- (b) those who are borderline for a change in diabetes treatment, for example from diet alone to oral hypoglycemic agents or from oral hypoglycemic agents to injectable treatment.
A more important consideration is whether conventional beta-blocker treatment is overall as effective in blood pressure lowering as other classes (see below).
Antihypertensive medication should nearly always be once daily. Most agents are intrinsically long-acting, and modified-release preparations of many short-acting agents are available.
Monotherapy versus combination therapy
Combination treatment with two different classes of agents is more effective than doubling the dose of one agent. This may be due in part to the problem that a proportion of patients will either not respond or have only a weak response to any single agent, but is made more attractive by the relatively low incidence of side-effects with most modern drugs. Initial therapy with two agents is likely to be useful in patients with high initial blood pressure or those with high cardiovascular risk: the blood pressure goal is likely to be achieved more quickly, there is a high risk of early events in these patients, and there is some evidence (e.g. from the VALUE study) that the event rate is reduced by prompt reduction in blood pressure. Fixed-dose combinations, now widely available, should be used whenever possible, and especially in moderate-risk (e.g. stage 2, SBP > 160 mmHg, DBP > 100 mmHg) or high-risk patients (see Fig. 11.3).
Interestingly, in the very large ACCOMPLISH trial (2008) where 60% of the participants had diabetes, an ACE-i/calcium-channel blocker (CCB) combination (benazepril up to 40 mg daily plus amlodipine up to 10 mg daily) was better than an ACE-i/thiazide combination (hydro-chlorothiazide up to 25 mg daily) in reducing major cardiovascular end points. (In addition, very low blood pressure levels were achieved in this study: mean blood pressure throughout was about 132/74 mmHg .) This study reinforces the European guidelines and should encourage increased use of fixed-dose combinations in high-risk patients, especially in the UK, where they are underused, possibly in part because prescriptions for people with diabetes are free of charge, but also because in the past academic teaching has frowned on them (Box 11.5).
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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)