Optimizing medical treatment for symptomatic angina: What’s new, what’s hot?
Agents such as beta-blockers and calcium antagonists have been the cornerstone of treatment for stable angina for some time. However, new options are emerging for patients who remain inadequately controlled on conventional therapies. At a recent Menarini-sponsored symposium held during the APSC Congress 2017 in Singapore, three experts discussed the current treatment landscape, as well as changing paradigms and new effective options for patients with symptomatic angina.
Studies have shown that patients with stable coronary artery disease (CAD) can be effectively managed with medical therapy, and do not require urgent revascularization. [N Engl J Med 2007;356:1503-1516] “In patients with stable angina, we aim to make them feel better and live longer, and this requires two avenues of therapy: symptomatic treatment and event prevention,” said Dr Yeo Khung Keong of the National Heart Centre in Singapore. This approach is reflected in major international guidelines (Figure 1) where aspirin or other antiplatelet therapy, as well as statins, and in some cases ACE inhibitors or ARBs, are recommended for event prevention. [Eur Heart J 2013;34:2949-3003]
In terms of symptomatic relief, beta-blockers, which decrease myocardial oxygen consumption, are usually first-line therapy for all patients with angina if possible. However, they may have some side effects including bronchospasm, decreased exercise capacity, erectile dysfunction, and masking of hypoglycaemia in diabetic patients. Calcium channel blockers cause arterial dilation and after-load reduction, and enhance coronary collateral flow, but are associated with side effects such as headache, palpitations, ankle oedema, and gingival hyperplasia. Nitrates are still frequently used but often cause headaches. “Choice of anti-anginal is down to patient comorbidities and anti-anginal parameters because none of the drugs we use confer long-term mortality advantage, and we have to be mindful of that,” said Professor Peter Collins of Imperial College London, UK.
Targeting heart rate in stable angina
Heart rate is an important prognostic marker in patients with stable CAD. High heart rate is predictive of mortality. Therefore, targeting heart rate is an important treatment goal. [Eur Heart J 2005;26:967-974] Increased heart rate worsens ischaemia, and since beta-blockers improve symptoms of ischaemia, Dr Wiwun Tungsubutra of Siriraj Hospital in Bangkok, Thailand, posed the question, “Can beta-blockers prevent the occurrence of cardiovascular [CV] events in patients with stable CAD?”
Both the ESC and ACC guidelines include statements about the potential role of beta-blockers in prevention but with the caveat that this is not supported by any data from large placebo-controlled trials. It is likely that these statements were extrapolated from early studies that showed a decrease in all-cause mortality with beta-blockers in patients with heart failure and reduced ejection fraction, and after myocardial infarction (MI).
However, newer studies show a different picture. For example, the 1986-published ISIS-1 trial involving 16,027 patients showed a clear survival benefit with beta-blockers after MI, while the more recent COMMIT study on 45,852 patients showed no survival benefit. [Lancet 1986;2:57-66; Lancet 2005;366:1622-1632]
The reason for these different findings is likely due to changes in the management of patients with MI. In the ISIS-1 study, no patients received reperfusion therapy or statins, and only 5 percent received antiplatelet therapy. According to contemporary management, almost all patients would receive these treatments.
In patients with stable CAD, the REACH and CHARISMA studies found no effect with beta-blockers on long-term CV events in patients with and without prior MI, respectively. [JAMA 2012;308:1340-1349; Circ Cardiovasc Qual Outcomes 2014;7:872-881] In the US National percutaneous coronary intervention (PCI) registry of patients aged 65 or older who had PCI for stable CAD, 71 percent were discharged on a beta-blocker. [JACC Cardiovasc Interv 2016;9:1639-1648] “There has been a significant increase in the use of beta-blockers between 2003 and 2013, but no significant decrease in CV outcomes. In fact, those discharged on a beta-blocker had a higher incidence of heart failure,” noted Tungsubutra. It should also be noted that adherence to beta-blocker post-MI is quite poor, possibly due to side effects.
Tungsubutra concluded that although beta-blockers remain the cornerstone in the management of patients after acute MI and those with heart failure and reduced ejection fraction, they should be used selectively in patients with chronic stable angina because they can provide symptomatic relief but do not reduce the risk of CV events.
Newer anti-anginal agents
Other anti-anginal agents available are ranolazine, trimetazidine, and ivabradine. “Trimetazidine appears to be effective in some patients, although there is limited good quality data, and caution should be exercised in the case of renal dysfunction,” said Yeo. “Ivabradine has a limited indication and may provide some benefits in patients who do not tolerate beta-blockers.” The BEAUTIFUL study showed that ivabradine reduced the risk of fatal and nonfatal MI events in the subset of patients with a heart rate of at least 70 bpm. [Lancet 2008;372:807-816] However, in the SIGNIFY study, ivabradine did not reduce CV events in patients with CAD. [N Engl J Med 2014;371:1091-1099]
Ranolazine is indicated in adults as add-on therapy for the symptomatic treatment of patients with stable angina who are inadequately controlled or intolerant to first-line anti-anginal therapies (such as beta-blockers and/or calcium antagonists). Ranolazine has a unique mechanism of action, explained Collins. In the presence of ischaemia, the sodium channel remains widely open, activating sodium-calcium exchange, leading to calcium overload which causes electrical instability, mechanical dysfunction, and upset of oxygen supply and demand. Ranolazine blocks the late sodium current, re-establishing normal contractile function, improving subendocardial blood flow, and reducing ischaemia, he said.
The efficacy and safety of ranolazine are supported by a large clinical trial database of more than 8,000 patients. In patients with stable angina, ranolazine significantly improved exercise duration at trough level, time to angina, and time to 1 mm ST-depression at 12 weeks vs placebo on top of standard therapy. [JAMA 2004;291:309-316] When added to a background of amlodipine in the ERICA study, ranolazine significantly decreased angina frequency vs placebo. [J Am Coll Cardiol 2006;48:566-575]
The largest ranolazine trial was the 12-month MERLIN-TIMI 36, which enrolled 6,065 patients with a history of chronic angina and acute coronary syndrome. [JAMA 2007;297:1775-1783] Ranolazine on top of standard therapy significantly reduced worsening angina, the need for new anti-anginal therapy, and recurrent ischaemia, and increased quality of life and treatment satisfaction vs placebo (Figure 2). There was also a significantly lower incidence of arrhythmias in the ranolazine group. The most frequent adverse events reported were dizziness, nausea, constipation, and syncope. Ranolazine also significantly reduced the risk of the composite primary endpoint of CV death, MI, or recurrent ischaemia at 12 months vs placebo. [JAMA 2007;297:1775-1783]
Ranolazine is unique in that it provides anti-anginal and anti-ischaemic effects without affecting heart rate, blood pressure or rate-pressure product. [Am J Cardiol 2005;95:311-316] “Ranolazine offers distinct advantages with regard to it having no effect on heart rate or blood pressure due to its novel mechanism of action. If you have a patient with low heart rate or low blood pressure, this would be an ideal second-line drug to choose,” Collins pointed out. “Adding ranolazine to a beta-blocker or calcium antagonist resulted in improvements in all outcomes assessed.”