Hypertension
Table 1: Preferred Drug Treatment in Hypertensive Patients1
Subclinical Organ Damage LVH
Asymptomatic atherosclerosis
ACEI, CA, ARB CA, ACEI
Microalbuminuria ACEI, ARB Renal dysfunction
Clinical Events Previous stroke Previous MI
Angina pectoris Heart failure
Atrial fibrillation:
Recurrent ARB, ACEI Permanent
ESRD/proteinuria Peripheral artery disease
Conditions ISH (elderly)
Metabolic syndrome
BB, non-dihydropiridine CA ACEI, ARB, loop diuretics, CA CA
Diuretics, CA, ACEI ACEI, ARB, CA
Diabetes ACEI, ARB Pregnancy
Ethnicity Blacks
CA, methyldopa, BB Diuretics, CA
ACEI = angiotensin-converting inhibitor; ARB = angiotensin receptor antagonist; BB = beta- blocker; CA = calcium antagonist; ESRD = end-stage renal disease; ISH = isolated systolic hypertension; LVH = left ventricular hypertrophy; MI = myocardial infarction.
Table 2: Compelling Contraindications to the Use of Some Antihypertensive Drugs1
Thiazide diuretics Beta-blockers
Compelling Gout
Asthma Possible
Metabolic syndrome Glucose intolerance Pregnancy
Peripheral artery disease
Calcium antagonists (dihydropiridines)
AV block (grade 2 or 3) Metabolic syndrome Glucose intolerance Athletes and physically active patients Chronic obstructive pulmonary disease Tachyarrhythmias Heart failure
Calcium antagonists AV block (grade 2 or 3) (verapamil, diltiazem) Heart failure ACE inhibitors
Pregnancy
Angioneurotic oedema Hyperkalaemia Bilateral renal artery stenosis
Angiotensin receptor Pregnancy antagonists
Diuretics (antialdosterone)
Hyperkalaemia Bilateral renal artery stenosis
Renal failure Hyperkalaemia ACE = angiotensin-converting enzyme; AV = atrioventricular.
was published, the most popular fixed-dose combination of antihypertensive drugs was the association of a blocker of the RAS (ACEI or ARB) and a low dose of thiazide. Associations of beta-blockers and calcium antagonists and beta-blockers and diuretics
16 ACEI, ARB, CCB
Any BP-lowering agent BB, ACEI, ARB BB, CA
Diuretics, BB, ACEI, ARB, antialdosterone agents
were also quite popular in some countries. The association of an ACE inhibitor and a diuretic will certainly remain a very commonly prescribed single-pill combination: new data from the Action in Diabetes and Vascular disease-preterAx and DiamicroN Controlled Evaluation (ADVANCE) and Hypertension in the Very Elderly Trial (HYVET) studies using perindopril and indapamide, respectively, in patients with type 2 diabetes and in very elderly patients have confirmed the clinical benefits of this association to lower cardiovascular outcomes.
However, the trend may change in the future after the publication of the ACCOMPLISH trial, which compared two fixed-dose combination therapies in >11,000 hypertensive patients with a high cardiovascular risk, i.e. the combination of benazepril plus amlodipine and that of benazepril plus hydrochlorothiazide.9
Both therapeutic regimens
controlled BP adequately in close to 80% of patients with only a 1mmHg difference in BP between groups. The tolerability profile was excellent with both treatments. Surprisingly, the incidence of the primary end-point (a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, hospitalisation for unstable angina, coronary revascularisation procedures and resuscitated sudden death) was 20% lower in the benazepril plus amlodipine group than in the benazepril plus hydrochlorothiazide group. The studied population was characterised by a large proportion of obese patients (50%) and patients with diabetes (60%). Interestingly, a post hoc analysis of renal events in ACCOMPLISH has also demonstrated a lower incidence of renal complications with the benazepril plus amlodipine combination, suggesting that this single-pill combination may become an interesting approach to prevent renal as well as cardiovascular complications.10
Thus, today, significant outcome reductions have been demonstrated with several combinations of antihypertensive drugs, including ACE inhibitors and ARBs and a diuretic, an ACE inhibitor and a calcium antagonist and a calcium antagonist and a diuretic. One question that could be asked is: which combination should be preferred and for which patient? So far, there are no clear answers to these two questions as few studies except for ACCOMPLISH have really compared combination therapies in various hypertensive populations. The favourable metabolic profile of the combination of an RAS blocker and a calcium antagonist makes this association very suitable for the management of patients at a high risk of developing metabolic problems, such as obese hypertensives or patients with a metabolic syndrome. In all other patient groups the association of an RAS- blocker and a low-dose diuretic will remain an excellent therapeutic choice. In anticipation of the predicted obesity epidemic, several associations of RAS blocker and a calcium antagonist are being developed by the industry and should reach the market within a couple of years. Thus, besides the single-pill combination of benazepril and amlodipine, which is already available on the American market, several new combinations are under clinical investigation combining for example the ACE inhibitor enalapril and the dihydropyridine lercanidipine,11
or an ARB (valsartan12 or olmesartan13 and eventually the renin inhibitor aliskiren and amlodipine.14
) and amlodipine The
antihypertensive efficacy and the excellent tolerability profile of these new associations have been demonstrated in clinical studies. As mentioned previously, one important characteristic of these associations is the reduction of the incidence of peripheral oedema induced by the calcium antagonist. Indeed, blockade of the RAS effectively prevents the development of leg oedema caused by the peripheral vasodilatation promoted by calcium antagonists.
EUROPEAN CARDIOLOGY
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