Optimizing the management of stable CAD and HF
Stable CAD: Importance of risk stratification
“The natural history of atherosclerosis tells us that there is a window of opportunity during which we can intervene to prevent CAD-related adverse events,” said Dr Choo Gim Hooi from the Cardiac Vascular Sentral Kuala Lumpur (CVSKL), Malaysia. “Although largely silent, stable CAD is not entirely benign. We need to risk-stratify our patients because we need to know who is at the highest risk for an event and mortality so we can provide aggressive intervention.”
There is overwhelming evidence that hypertension, dyslipidaemia, and glucose intolerance significantly increase the risk of cardiovascular (CV) events. Hypertension, in particular, affects approximately 30–40 percent of the adult population. However, most patients with stable CAD have overlapping risk factors, which increase their CV risk. Professor Giuseppe Mancia from the University of Milano-Bicocca in Milan, Italy, noted that “patients who have hypertension, dyslipidaemia, and glucose intolerance are at very high risk, but evidence from randomized controlled trials clearly shows that treating each of these risk factors has a protective effect.”
Professor Claudio Borghi from the University of Bologna, Italy, cautioned that “management of hypertension is very important for improving CV outcomes, but is not sufficient to reduce the overall CV burden because of the problem of residual CV risk.” Organ damage is one important cause of residual CV risk and is linked to abnormalities in central blood pressure (BP), which can be used to determine the haemodynamic performance of a patient. It may also have a role as a CV risk factor, particularly in the young and elderly populations. “Increased central BP and pulse wave velocity have been shown to increase the relative risk of major CV complications and may be associated with a worse prognosis,” said Borghi.
The importance of low-density lipoprotein (LDL) cholesterol levels in reducing CV risk was noted by Associate Professor Yiu Kai Hang from the University of Hong Kong, Hong Kong. He also highlighted new risk factors linked to an increased risk of myocardial infarction, including circulating microRNAs, nonsteroidal anti-inflammatory drugs, and chronic inflammatory diseases such as systemic lupus erythematosus, rheumatoid arthritis, and psoriasis.
Pharmacological management of stable CAD
“There is some discordance between the level of evidence and recommendations made for the treatment of stable CAD in international guidelines,” noted Professor Peter Collins from Imperial College and the Royal Brompton Hospital, London, UK.
Beta-blockers and calcium channel blockers are recommended for first-line therapy (class IA evidence in the ESC guidelines). However, US guidelines rate the level of evidence for these therapies as class IB. The rating for ranolazine, a novel anti-angina therapy that inhibits the ischaemia-induced sodium influx that occurs in cardiac myocytes, also differs (IIaA in the US guidelines and IIaB in the ESC guidelines).
“The US guidelines are probably correct,” said Collins. “Ranolazine, for example, is the only novel anti-angina therapy recommended for clinical use in the US in the past 20 years. Uniquely, it does not have any significant effects on heart rate or BP and is a highly effective second-line and add-on therapy.”
Ranolazine has significant antianginal actions in a clinical trial database of almost 10,000 subjects. It is an effective antianginal when compared to placebo and in addition to standard antianginal therapy such as beta-blockers, calcium channel blockers, and nitrates. It also has a significant antianginal action in diabetic subjects and in patients with acute coronary syndromes. It has also been shown to improve diabetic control by reducing HbA1c and has antiarrythmic properties, reducing atrial fibrillation and supraventricular and ventricular tachyarrythmias.
Professor Jong-Won Ha from the Yonsei University College of Medicine, Seoul, South Korea, emphasized the importance of distinguishing between older and newer-generation beta-blockers when treating hypertension. “Older generation beta-blockers such as atenolol have been shown to be inferior to angiotensin receptor blockers [ARBs] for uncomplicated hypertension, suggesting that they are no longer suitable for first-line therapy,” he said. “However, third-generation vasodilating beta-blockers such as nebivolol have a favourable effect on endothelial function and show much promise.”
Central BP elevation can also be successfully treated with vasodilatory beta-blockers. Dr Antonia Anna Lukito of Pelita Harapan University, Tangerang, Indonesia, reviewed study data showing that nebivolol, which modulates nitric oxide release, effectively reduces central BP and aortic stiffness without any of the limitations associated with traditional beta-blockers. Nebivolol also has favourable effects on lipids and glucose control in patients with hypertension.
“Revascularization procedures should only be considered for patients who have symptoms that are not satisfactorily controlled with optimal medical therapy,” said Collins. He reported data from the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial, which indicated that coronary interventions had a neutral effect on patient outcomes. [N Engl J Med 2007;356:1503-1516]
Group Captain Krisada Sastravaha, Bhumibol Adulyadej Hospital, Thailand, agreed that revascularization is not suitable for most patients with stable CAD. However, he noted that in the NUCLEAR substudy of the COURAGE trial, percutaneous coronary intervention (PCI) was found to improve outcomes in patients with significant ischaemia. [J Nucl Cardiol 2006;13:685] “PCI is a mechanical revascularization procedure aimed at relieving acute ischaemia. Optimal medical therapy is clearly the best first-line option for most patients with stable CAD, but medical therapy is insufficient in certain patients, such as those with left ventricular dysfunction,” he said.
The type of intervention selected also requires careful targeting. In the Synergy Between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery (SYNTAX) trial, clinical outcomes were compared among patients with complex CAD randomized to revascularization with coronary artery bypass grafting (CABG) or PCI. [Lancet 2013;381:629-638] Although the researchers found fewer adverse events following CABG, outcomes were similar between the two interventions when patients had a SYNTAX score <22. “CABG remains the standard of care for patients with complex, multivessel disease but in less complex cases, such as patients who have left main disease with low or intermediate SYNTAX scores or triple vessel disease with a low SYNTAX score, PCI is a reasonable alternative treatment,” said Yiu.
Optimal medical therapy after revascularization
Optimal medical therapy (OMT) is defined as a combination therapy with at least one antiplatelet drug, such as aspirin (or thienopyridine after PCI), and a beta-blocker, statin, and angiotensin converting enzyme (ACE) inhibitor or ARB. The regimen is aggressive and is used to prevent future CV events, not for ischaemic control.
“There is compelling evidence that optimal medical therapy reduces postrevascularization mortality rates and should be initiated in all patients following revascularization unless there are any contraindications,” said Collins. Analyses of the 5-year clinical outcomes from the SYNTAX trial have shown that postrevascularization OMT significantly reduces the risk of death (hazard ratio [HR], 0.64, 95 percent confidence interval [CI], 0.48–0.85; p=0.002) (Figure 1) as well as the composite endpoint of death, myocardial infarction (MI), and stroke (HR, 0.73, 95 percent CI, 0.58–0.92; p=0.007) (Figure 2). [Lancet 2013;381:629-638]
“However, changes in clinical practice have been modest despite the publication of such findings and further work is required to determine how best to incorporate OMT into interventional strategies and to improve the translation of clinical evidence into practice,” concluded Collins.
Management of HF
“China is facing an epidemic of HF, and the prevalence is only likely to increase given that a significant proportion of the population is classified as high risk,” said Dr Jiefu Yang, Beijing Hospital, China. Hypertension and CAD are the leading causes of HF in the region, and diuretics, digitalis, and nitrates the primary therapies. However, the use of digitalis is declining and that of beta-blockers, ACE inhibitors, ARBs, and aldosterone antagonists are increasing. The number of patients reaching the target doses of these agents remains quite low and they are more frequently used for HF-reduced ejection fraction (REF) rather than HF-preserved ejection fraction (PEF) patients.
Professor Carolyn Lam, National Heart Centre, Singapore, noted the importance of viewing HF-PEF as a real HF and not a collection of comorbidities. Although there is at present no specific treatment for HF-PEF that improves survival, LCZ696 was shown in the phase II PARAMOUNT trial to significantly reduce N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels after 12 weeks compared with valsartan. [Lancet 2012;380:1387-1395] HF-PEF is now thought to result from systemic endothelial activation and inflammation, and drugs such as LCZ696, an angiotensin receptor neprilysin inhibitor, may be beneficial by addressing this endothelial dysfunction. A phase III PARAGON trial of LCZ696 is currently underway. Professor Imran Zainal Abidin from the University of Malaya, Kuala Lumpur, Malaysia noted that there is currently some controversy regarding whether or not LCZ696 should be recommended as first-line therapy. Those advocating caution cite concerns regarding possible angioedema and cognitive adverse events. The use of beta-blockers in HF patients with atrial fibrillation is also controversial given that they do not seem to significantly reduce mortality risk in this population.
Professor Panos Vardas from the Heraklion University Hospital, Greece, highlighted promising developments expected to impact CV medicine in the next two decades. PCSK9 inhibitors, monoclonal antibodies, and novel antithrombotic and antiarrhythmic drugs are all expected to alter medical therapy, while technological advances are expected to lead to the miniaturization of pacemakers, the advent of leadless and batteryless devices, increased use of multisensors, high-quality imaging, and increasing use of regenerative biology.