Paradigm shift in the front-line maintenance of at-risk CVD patients

CVD in the Australian population Elevated blood pressure (BP) is the most common risk factor for cardiovascular-related morbidity and mortality. In Australia, the burden of cardiovascular disease (CVD) is only surpassed by all cancers combined.1 CVD affects 1 in every 6 Australians, and due to the ageing population it is predicted to affect 1 in 4 by 2050, or 6.4 million people.2 CVD is the largest cause of mortality, accounting for 38% of deaths, of which 60% did not reach average life expectancy.2 Thus CVD represents a significant disease burden and accounts for 11% of the total health budget.2

Summary of findings

The development of angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) has transformed the treatment of CVD. For a number of years, the mainstay of treatment of at-risk patients with hypertension and co-morbidities has been ACE inhibitors.^3-5 A number of large, double-blinded, randomised prospective trials in recent years have compared various ACE inhibitors and ARBs for their capacity to lower BP and CVD risk. In analysis of these trials, the ARB telmisartan is not only as effective at lowering CVD risk in at-risk patients as the reference ACE inhibitor (ramipril), but also shows improved tolerability.⁶

CVD risk factors and limitations of current management of elevated BP and CVD risk

Patients with elevated BP often have other risk factors that increase CVD risk, including high cholesterol, a sedentary lifestyle, obesity, diabetes, nephropathy, smoking, heart failure and age. This at-risk cohort is often managed with ACE inhibitors, which have a well-established track record of cardiovascular protection and reducing CVD-related morbidity and mortality. Despite these benefits to CVD outcomes, ACE inhibitors are less efficacious than ARBs at lowering BP and managing early morning BP surges.⁷ In addition, ACE inhibitors can be associated with adverse effects including angioedema, cough, dizziness, hypotension, taste disturbances and skin rash. Many patients discontinue ACE inhibitor use due to these adverse effects.^8-10 

ARBs in maintenance of BP and CVD risk

Mounting evidence suggests that the BP-lowering efficacy of ARBs varies significantly, with olmesartan¹¹ and telmisartan¹² showing greater efficacies than losartan, valsartan, and irbesartan. ARBs reduce BP to a similar or greater extent than ACE inhibitors. The Prospective Randomised Investigation of the Safety and Efficacy of Micardis versus Ramipril using Ambulatory Blood Pressure Monitoring (PRISMA) I and II studies,⁷ and the Ongoing Telmisartan Alone and in Combination with Ramipril Global End Point Trial (ONTARGET)¹⁰ both reported greater reductions in BP with telmisartan (ARB) compared with ramipril (ACE inhibitor).

In addition to the comparative BP-lowering efficacy of ARBs compared to ACE inhibitors, ARBs are now known to reduce morbidity and mortality associated with CVD, renal and cerebrovascular incidents by blockading the renin-angiotensin system (RAS).¹³

ARBs and patients at increased risk of CVD

ONTARGET, the largest study to date, compared an ARB (telmisartan) with the reference ACE inhibitor (ramipril) in patients with a broad range of risk factors, although elevated BP was not an inclusion criterion. This cohort is similar to that of the Heart Outcomes Prevention Evaluation (HOPE) study that established ramipril as the gold standard RAS blocker.⁵ Telmisartan performed equivalently to ramipril in the composite primary endpoint of CV-related mortality, myocardial infarction, stroke or hospitalisation for heart failure. ONTARGET also showed significantly improved tolerability and compliance with telmisartan compared to ramipril, largely due to reduced occurrences of coughs and angioedema.¹⁰

ARBs and patients at very high risk of CVD

The Evaluation of Losartan in the Elderly II (ELITE II) study included patients with category II–V heart failure and ejection fractions of less than 40%. This study showed that all-cause mortality and hospitalisation after heart failure was similar for losartan (ARB) and captopril (ACE inhibitor),⁹ but there was a significant increase in tolerance with losartan (P<0.001). The Valsartan Heart Failure Trial (VaHeFT) included patients with category II–IV heart failure receiving ACE inhibitors. There was no reduction in mortality in the valsartan (ARB) treated group compared to the placebo control group; however, there was a significant improvement in morbidity, largely due to reduced hospitalisations.¹⁴ The overall Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) study provided further supportive evidence for the additional protective effects of ARB treatment in patients with heart failure receiving ACE inhibitors.¹⁵ 

Two studies examined the CV protective effects of ARBs compared with the ACE inhibitor captopril in post myocardial infarction patients. The Optimal Therapy in Myocardial Infarction with the Angiotensin II Antagonist Losartan (OPTIMAAL) study⁸ showed a trend towards reduced mortality with captopril compared to losartan (P=0.07), but a significantly greater tolerability for losartan (P<0.0001). The Valsartan in Acute Myocardial Infarction Trial (VALIANT) found similar mortalities and morbidities in patients treated with valsartan or captopril.¹⁶ These findings suggest that ACE inhibitors should remain the front-line treatment in patients post myocardial infarction and that losartan should be avoided in this patient group.

In summary, ONTARGET, the largest prospective study of ARBs, demonstrated that telmisartan is comparable to the gold standard antihypertensive ramipril in preventing CV death, MI, stroke or heart failure hospitalisation in patients over 55 years of age with coronary artery disease, cerebrovascular disease, peripheral artery disease or diabetes with end organ damage. VALIANT showed that valsartan is as effective as captopril in post myocardial infarction patients. ELITE II, ValHeFT and CHARM suggest that ARBs are as efficacious as ACE inhibitors in heart failure patients. On the basis of these equivocal efficacies at reducing CV risk, ACE inhibitors are recommended to clinicians as front-line treatment due to lower treatment costs. In the "real world", ARBs are linked to greater tolerability and compliance, and the increased cost associated with ARBs is likely to be offset by reduced use of medical assistance associated with adverse effects.

In conclusion, ARBs should be used as front-line management of elevated BP and CV risk. However, practitioners should be wary of implying there is a "class effect", that is, extrapolating results from trials of one particular drug to other drugs within the same class.¹⁷ In the interests of evidence-based practice, it is recommended that health professionals prescribe medications that have been properly tested in randomised controlled trials, at the dosages that have shown clinical benefits in the trial in the appropriate patient populations.¹⁰

References       

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