Selective If inhibition:new frontiers inthe management of coronary disease

THE LAST 30 YEARS HAVE SEEN SPECTACULAR PROGRESS IN THE management of stable coronary artery disease (CAD), with numerous new pharmacological and interventional options becoming available. The most recent statistics from the American Heart Association (AHA) report a 33% reduction in rates of mortality due to CAD in the 10 years to 2004,1 which can be largely attributed to these advances. Despite this progress, the disease remains an important contributor to mortality and morbidity in the Western world. Indeed, the AHA statistics also place CAD as the single largest killer of American adults, with 1 in 5 deaths being attributable to CAD.1 Clearly, there is little room for complacency in our management of stable CAD, and we need to continue to seek original and innovative ways of saving lives in this population. A striking demonstration of this situation came from analysis of data from patients included in the REduction of Atherothrombosis for Continued Health (REACH) Registry in 44 countries between 2003 and 2004.2 This 1-year, international study recruited a large subset of more than 38 000 patients with stable CAD. The majority of the REACH patients were receiving contemporary, evidence-based, preventive drug therapy, including antiplatelet therapy, lipid-lowering agents, and angiotensin-converting enzyme inhibitors, and about half were receiving β-blockers. Despite this, all-cause mortality at 1 year was 2.89% and cardiovascular mortality was 1.93%. Patients with stable CAD also had a 4.52% rate of a composite end point of cardiovascular death, myocardial infarction (MI), and stroke. The REACH authors rightly concluded that continued efforts are needed to improve secondary prevention and clinical outcomes.2 The implications of the REACH data in terms of burden of disease are alarming, considering that the lifetime risk of developing CAD for American adults aged over 40 is 49% for men and 32% for women.1 One conclusion is that current management strategies in stable CAD are failing to reach the expectations of cardiologists and patients alike.3 Current guidelines recommend a two-pronged management strategy for patients with stable CAD, who require one treatment to relieve symptoms alongside another to reduce long-term morbidity and mortality.4 Despite the progress in the field, 50% of patients remain symptomatic with treatment, and rates of mortality are highly unsatisfactory. These shortcomings can be traced to a number of factors. Pharmacological therapy is abound with problems of subtherapeutic dosing and compliance. Furthermore, the optimization of treatment can be hindered by insufficient efficacy in patients with refractory angina and by a long list of contraindications, for example, β-blockers are contraindicated in patients with asthma, peripheral vascular disease, and severe bradycardia, which may limit their use in those patient populations. Another factor is poor tolerability, which may lead to treatment discontinuation and reduce the efficacy of even the most rigorous management strategy. Surgical intervention does not necessarily resolve these problems: intervention is not always possible, and most revascularized patients still require antianginal treatment after the procedure. Indeed, as the Clinical Outcomes Utilizing Revascularization and AGgressive drug Evaluation (COURAGE) trial recently demonstrated,5 there is no benefit of percutaneous coronary interven- E D I T O R I A L Address for correspondence: Prof Roberto Ferrari, Chair of Cardiology, Arcispedale S. Anna, University of Ferrara, Corso Giovecca 203, 44100, Ferrara, Italy and Fondazione Salvatore Maugeri, IRCCS, Brescia, Italy (e-mail fri@dns.unife.it) Prof Kim Fox, Professor of Cardiology, Royal Brompton Hospital, London SW3 6NP, UK (e-mail k.fox@rbht.nhs.uk) Medicographia. 2008;30:189-195. Selective I f inhibition: new frontiers in the management of coronary artery disease b y R . F e r r a r i a n d K . F o x , I t a l y a n d U n i t e d K i n g d o m Kim FOX, MD, FESC Professor of Cardiology Royal Brompton Hospital London, UK Roberto FERRARI, MD, PhD Chair of Cardiology Arcispedale S. Anna University of Ferrara and Fondazione Salvatore Maugeri, IRCCS Brescia, ITALY tion (PCI) on top of guideline-based optimized pharmacological therapy, in terms of reduction in risk of mortality, MI, or major cardiovascular events. This demonstrates how important it is to raise our standards in preventive cardiology through improvement of established lifestyle and therapeutic intervention and control of other clinical parameters, which can improve cardiovascular risk assessment and management. The ideal treatment for stable CAD would be one that provided both anti-ischemic and antianginal efficacy, as well as improvement in prognosis by reducing cardiovascular events. Heart rate (HR) is one of the clinical parameters that is most frequently assessed in daily practice. Being the main determinant of ischemia, HR reduction is established as an important therapeutic component of the prevention of ischemia. A strong association between elevated HR and increased risk of all-cause mortality, cardiovascular mortality, and development of cardiovascular disease has been shown in the general population, as well as in patients with hypertension, diabetes, and CAD.6,7 Experimental data have demonstrated the involvement of HR in the development of atherosclerosis with reduction in its progression after pharmacological or surgical HR reduction. The impact of β-blockers and of some calcium blockers on mortality in post-MI patients has been suggested to be related to reduction in resting HR. Consistent with this understanding of the important role of HR, ivabradine, the first selective and specific If inhibitor, opens up promising opportunities in the management of CAD.