Dr John Cox reports on a number of clinical trials which have investigated the pros and cons of treatment with ARBs compared to or combined with ACE inhibitors.
General practitioners are by now very familiar with the drugs used in the management of high blood pressure, lipid and glucose levels. However, consideration should also be given to the use of drugs which have been shown in clinical trials to reduce morbidity and mortality from cardiovascular disease (CVD) in addition to drugs used for treatment of elevated blood pressure, lipids and glucose.
The present position with regard to cardioprotective drug therapy is given in Chapter 19 of the 2007 version of the European Guidelines on CVD Prevention in Clinical Practice.
While some of these drugs (e.g. aspirin) are appropriate for all individuals at high total risk, whether from established CVD or at high risk of developing CVD, others (e.g. beta-blockers post myocardial infarction) are specifically indicated in selected patients.
These recommendations can be summarised as follows:
(1) Aspirin for virtually all patients with established CVD, and in persons at >10 per cent SCORE risk once blood pressure has been controlled;
(2) Beta-blockers after myocardial infarction and, in carefully titrated doses, in those with heart failure;
(3) Angiotensin converting enzyme (ACE) inhibitors in those with left ventricular dysfunction and in diabetic patients with hypertension or nephropathy;
(4) Anticoagulants in those at increased risk of thromboembolic events, particularly atrial fibrillation.
h4. ACE inhibitors in heart failure or left ventricular dysfunction
A number of clinical trials (e.g. CONSENSUS, SAVE and AIRE studies) have shown conclusively that ACE inhibitor therapy in patients with symptoms or signs of heart failure, or left ventricular dysfunction, due to any cause including coronary heart disease (CHD) will significantly reduce risk of death, recurrent myocardial infarction and progression to persistent heart failure.
On the basis of this evidence, most general practitioners would not hesitate to prescribe ACE inhibitor treatment to patients with heart failure or left ventricular dysfunction.
h4. CHD without heart failure or left ventricular dysfunction
The efficacy of ACE inhibitors compared with placebo in patients with CHD without evidence of left ventricular dysfunction or heart failure has been investigated in several major trials, with mixed outcomes. The best known of these to general practitioners is the Heart Outcomes Prevention and Evaluation (HOPE) trial.
In this study, where about 80 per cent of patients had a history of coronary disease without evidence of left ventricular systolic dysfunction or heart failure, there was a relative risk reduction of 22 per cent in cardiovascular morbidity and mortality with the ACE inhibitor, ramipril.
Another study familiar to general practitioners is the the EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease (EUROPA). ACE inhibitor treatment was associated with a relative risk reduction of 20 per cent in this trial, where all patients had documented coronary heart disease and no apparent heart failure.
In contrast, two other studies found no significant difference between ACE inhibitor and placebo treatment. In the Prevention of Events with Angiotensin Converting Enzyme inhibition (PEACE) study, there was no significant reduction in cardiac outcomes with trandolapril in patients with coronary artery disease and preserved left ventricular.
Similarly, in the QUinapril Ischemic Event Trial (QUIET), there was also no significant reduction with quinapril in ischemic events and progression of coronary artery disease in coronary angioplasty patients without systolic left ventricular dysfunction.
However, a meta-analysis of data from the HOPE, EUROPA, PEACE and QUIET trials demonstrated 14 per cent reductions in all-cause mortality and myocardial infarction, a 23 per cent reduction in stroke, and a seven per cent reduction in revascularisation procedures, thus providing strong evidence for the benefits of ACE inhibition in this group of patients.
h4. ARBs in heart failure or left ventricular dysfunction
It has been postulated that angiotensin receptor blockers (ARBs), which block all direct angiotensin receptor blockade, might be more effective than ACE inhibitors, which do not. Also, ACE inhibitors have the additional action of enhancing bradykinin, which leads to the side effects of cough and angioedema. Treatment with ARBs in patients with heart failure or left ventricular dysfunction has been shown to be effective in a number of trials to date.
Thus, in the Effects of Candesartan in patients with chronic Heart failure And Reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyMe inhibitors (the CHARM-Alternative trial), ARB treatment was generally well tolerated and reduced cardiovascular mortality and morbidity in patients with symptomatic chronic heart failure and intolerance to ACE inhibitors.
Similarly, in the VALsartan HEart Failure Trial (Val-HeFT), where valsartan was compared to placebo in patients taking prescribed background therapy for New York Heart Association class II to IV heart failure, treatment was shown to reduce the risk of heart failure hospitalisation and improved clinical signs and symptoms of heart failure.
Finally, the results of the large multi-centre, randomised VALIANT trial showed that the ARB valsartan was effective in reducing mortality in patients with CHF or reduced left ventriculation function following myocardial infarction.
h4. ARBs in CHD without heart failure or left ventricular dysfunction
The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) investigated the benefits of treatment with the ARB telmisartan and the ACE inhibitor ramipril alone and in combination.
The ONTARGET trial itself and also its sister trial, Telmisartan Randomised AssessmeNt Study in ACE-iNtolerant subjects with cardiovascular Disease (TRANSCEND), form the largest study programme to date, comparing ARBs and ACE inhibitors and therapy in high-risk patients with controlled blood pressure (the ONTARGET programme).
ONTARGET enrolled 25,620 patients with coronary heart disease or diabetes, plus additional risk factors, who were over the age of 55 years but did not have evidence of heart failure. In this study, patients were randomised to receive ramipril 10 mg per day (the same dose used in HOPE), telmisartan 80 mg a day, or the combination of the two.
Results showed that mean blood pressure was lower in the telmisartan group (a 0.9/0.6-mm-Hg-greater reduction) and in the combination-therapy group (a 2.4/1.4-mm-Hg-greater reduction) than in the ramipril group. At the end of the study, the primary end point (a composite of cardiovascular death, myocardial infarction, stroke or hospitalisation for heart failure) had occurred in a similar number of patients in all three groups of patients.
Compared with the ramipril group, telmisartan patients had lower rates of cough and angioedema and a higher rate of hypotensive symptoms, and patients given the combination treatment had higher rates of hypotensive symptoms, syncope, renal dysfunction and hyperkalemia, with a trend toward an increased risk of renal function requiring dialysis.
The main implication from this study for general practitioners is that in patients who have vascular disease or high-risk diabetes but do not have heart failure, telmisartan is an equally effective alternative to ramipril. The other important finding is that there is no additional advantage (and there is some harm) from the combination of telmisartan and ramipril used in full doses in this population, as compared with ramipril alone.
h4. Use of ACE inhibitors and ARBs in general practice
The ACE inhibitor ramipril is the drug 11th most commonly prescribed by general practitioners in Ireland, accounting for 494,247 prescriptions (1.32 per cent of total) at an ingredient cost of €8,065,145 (1.21 per cent of the total). While there is no way of establishing for which conditions these prescriptions were issued, most of these were probably for patients with hypertension and/or heart failure.
Similarly, while the extent to which general practitioners prescribe ACE inhibitors to patients at high risk of vascular events (i.e. those with coronary, peripheral or cerebrovascular disease or diabetes with end-organ damage) without evidence of left ventricular dysfunction or heart failure is not known, they are probably underprescribed, especially given the evidence that is now available.
The ONTARGET finding that telmisartan is an equally effective alternative to ramipril and that patients had lower rates of side effects (cough and angioedema) would be expected to affect how doctors will choose between an ACE inhibitor and an ARB in this population.
Most general practitioners would start a patient on an ACE inhibitor on the grounds that it was less expensive (telmisartan 80 mg: €24.99 per month, versus generic brand of ramipril 10 mg: €14.83 per month). However, as around 15 per cent to 25 per cent (and higher in certain groups) of people will not tolerate ACE inhibitors because of cough and a smaller number run the risk of angioedema, tolerability is an important consideration.
h4. Conclusion
There is compelling evidence that patients at high risk of vascular events (i.e. those with coronary, peripheral or cerebrovascular disease or diabetes with end-organ damage) without evidence of left ventricular dysfunction or heart failure benefit from treatment with an ACE inhibitor or an ARB (but not both). The ONTARGET finding that the ARB telmisartan is an equally effective alternative to the ACE inhibitor ramipril with lower rates of side effects (cough and angioedema) will have to be balanced against considerations of cost by general practitioners.
* Dr John Cox is a HEARTWATCH GP Co-ordinator and a member of the British Hypertension Society. He is presently recruiting patients for a study supported by Boehringer Ingelheim.
About Gary Culliton
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