The cardiovascular and cardiorenal disease continuum comprises the transition from cardiovascular risk factors to endothelial dysfunction and
atherosclerosis, to clinical complications such as
myocardial infarction (MI) and
stroke, to the development of persistent target-organ damage and, ultimately, to chronic
congestive heart failure (CHF),
end-stage renal disease or premature death. The renin-angiotensin-aldosterone system (RAAS) is involved in all steps along this pathway, and RAAS blockade with
ACE inhibitors or
angiotensin AT(1)-receptor
antagonists (angiotensin receptor blockers; ARBs) has turned out to be beneficial for patient outcomes throughout the disease continuum. Both
ACE inhibitors and ARBs can prevent or reverse endothelial dysfunction and
atherosclerosis, thereby reducing the risk of cardiovascular events. These drugs have further been shown to reduce end-organ damage in the heart, kidneys and brain.
Aldosterone antagonists such as
spironolactone and
eplerenone are increasingly recognized as a third class of RAAS inhibitor with potent risk-reducing properties, especially but not solely with respect to the inhibition of cardiac remodelling and the possible prevention of
heart failure. In
secondary prevention, head-to-head comparisons of
ACE inhibitors and ARBs, such as the recent ONTARGET study, provided evidence that, in addition to better tolerability, ARBs are non-inferior to
ACE inhibitors in the prevention of clinical endpoints such as MI and
stroke in cardiovascular high-risk patients. However, the combination of both
ramipril and
telmisartan at the maximally tolerated dosage achieved no further benefits and was associated with more adverse events such as symptomatic
hypotension and renal dysfunction. In acute MI complicated by
heart failure, the VALIANT trial has shown similar effects of ACE inhibition with
captopril and ARB treatment with
valsartan, but dual RAAS blockade did not further reduce events. In CHF, meta-analyses of RESOLVD, ValHeFT and CHARM-ADDED have shown that combined RAAS inhibition with an
ACE inhibitor and ARB significantly reduced the morbidity endpoint in certain patient subgroups compared with standard
therapy. However, in clinical practice, dual RAAS blockade is rarely employed, as seen, for instance, in the CORONA trial. The
RALES and EPHESUS trials, investigating the effects of
aldosterone blockade on cardiovascular outcomes in CHF patients, revealed that the addition of an
aldosterone antagonist to standard
heart failure therapy conferred powerful relative risk reductions for both morbidity and mortality. Future studies will elucidate whether this also holds true for patients who are asymptomatic or who have
heart failure with preserved ejection fraction. In selected patients with renal disease, several studies have suggested that combined RAAS blockade brings about additional renoprotective antiproteinuric effects independent of blood pressure reduction, and large trials with robust endpoints are underway. In summary, combined
therapy with several RAAS inhibitors is not recommended for all patients along the cardiorenovascular continuum. Patients with CHF with incomplete neuroendocrine blockade, as indicated, for example, by repetitive cardiac decompensation or refractory symptoms, might benefit from dual
therapy as long as safety issues are well controlled. Finally, novel pharmacological agents such as the
direct renin inhibitor aliskiren may provide additional therapeutic tools, but their role has yet to be established.