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Angina – getting ‘tighter’ control of the ‘tightness’

The days of our patients carrying around their little pink bottle in their pockets as a hopeful quick relief from chest tightness have largely become a thing of the past. As an interventional cardiologist, I feel that I have not done my job properly if one of my stable patients has to resort to a puff of GTN (glyceryl trinitrate). The advances in recent years in both interventional abilities, but almost more importantly, medical therapies, have allowed us to improve massively on patient quality of life.

For any patient presenting with chest discomfort, the focus from the outset becomes ensuring that it is not due to a cardiac cause. Myocardial ischaemia results in angina pectoris, or classically a central chest ‘tightness’ that occurs with effort. We are all aware of a spectrum of variability in presenting symptoms outside of these typical descriptions, but the aim is timely diagnosis and treatment in order to reduce morbidity and mortality. Some of our patients will present with exertional shortness of breath, nausea, diaphoresis or even fatigue, as opposed to the classical chest discomfort. The initial presentation of myocardial ischaemia may be of a stable anginal pattern or an acute coronary syndrome.

For most patients, we are able to minimise frequency and severity of stable anginal symptoms through a combination of conventional medical therapies, which include beta-blockers, calcium channel blockers and nitrates. Newer agents such as ranolazine are effective when added to standard therapy in reducing symptoms and improving exercise tolerance.

All of our patients with coronary artery disease should receive optimal medical therapy. This sweeping statement not only refers to the use of appropriate medication, but also to the often less popular and poorly-sustained behavioural interventions that have been shown to have a significant impact in reducing the risk of cardiovascular events. We need to carefully and aggressively target risks associated with hypertension, smoking, diabetes and inactivity. Progression of coronary disease, even in our patients who have undergone revascularisation, is an important determinant of subsequent clinical outcome.

Conditions that may precipitate or aggravate myocardial ischaemia, such as hypertension, tachyarrhythmias like atrial fibrillation, thyroid irregularities, anaemia or valvular heart disease, should be tackled. Lifestyle modification forms a crucial cornerstone of standard treatment. The gradual build-up of regular exercise improves fitness and results in lower oxygen requirements for a given workload.

Initial investigation

History and physical examination will often provide a convincing story that will make us immediately suspicious. Of course, some patients are less obvious. Stress testing is typically the first diagnostic test in assessing patients who are able to manage the treadmill. Beyond this, functional testing with dobutamine stress echo allows us to visualise left ventricular systolic function with increasing doses of dobutamine and faster heart rates. We look for cardiac wall motion abnormalities to ensure there is no apparent strain with tachycardia. Cardiac MRI has fast become a very useful tool in assessing patients for inducible ischaemia, particular those following previous coronary interventions or with known moderate disease.

CT coronary angiography has helped in providing a single diagnostic tool in ruling out significant underlying coronary disease and will regularly form a part of our diagnostic algorithm. In patients with positive testing, the next step in firming-up our suspicion is a standard coronary angiogram — a test which itself has evolved over years. Most studies are now done via radial arterial access, which has proven easier on patients and is less likely to cause vascular issues.

Guidelines for therapy — tried and tested

European and American guidelines are in agreement that beta-blockers form the first-line therapy in reducing anginal episodes and improving exercise tolerance. Beta-blockers relieve symptoms through a reduction in both heart rate and contractility. They are the only medications shown to prevent re-infarction and to improve survival in patients who have had previous heart attacks. In terms of choice, all beta-blockers appear to be equally effective in exertional angina.

Calcium channel blockers are used in combination with beta-blockers or as a substitute in situations in which beta-blockers are contraindicated or use is limited due to side-effects. Symptoms are improved through the effect of coronary and peripheral vasodilatation and reduction in myocardial contractility. Nowadays, the use of long-acting diltiazem or verapamil, or a second-generation dihydropyridine (amlodipine or felodipine), is preferred. Short-acting dihydropyridines such as nifedipine should be avoided, as when used in conjunction with beta-blockers, they can increase mortality after myocardial infarction (MI) and increase the frequency of acute MI in hypertensive patients.

Although differing physicians will have differing approaches, the use of beta-blockers as first-line would be preferential, as the survival benefit seen with beta-blockers in patients with previous MI or left ventricular systolic dysfunction has not been replicated with calcium channel blockers. Addition of a further agent such as a calcium channel blocker or nitrate to the beta-blocker is indicated if symptoms persist with monotherapy. If symptoms are persistent despite two agents, a third anti-anginal can be introduced, but the threshold for pushing on to coronary angiography at that point is low.

Nitrates were first used for the treatment of angina in the late 1800s and they are still widely used today. The mode of action is via venodilation, coronary vasodilatation and arteriolar dilatation, but the primary anti-ischaemic effect comes via decreased myocardial oxygen demand by producing systemic vasodilation — the main reason they are contraindicated when used in conjunction with vasodilators for erectile dysfunction. Nitrates are particularly useful in the setting of primarily vasospastic angina.

GTN spray still forms the front line of treatment in the setting of acute anginal symptoms and when patients arrive emergently to hospital with an acute coronary syndrome, they will have invariably received multiple puffs of sublingual nitrate on the ambulance journey.

Long-acting nitrates are typically added to baseline beta-blocker therapy to control stable anginal symptoms. Chronic nitrate use in oral or topical patch form improves exercise tolerance and time-to-onset of angina. The long-term utility of nitrates is somewhat limited by the gradual induction of nitrate tolerance. Interestingly, there has been no difference in efficacy among the various oral or dermal nitrate preparations and so use should depend on physician, and of course patient, preference.

There is conflicting data available regarding the benefit of ACE inhibitors in the reduction of exercise-induced ischaemia. Overall, it would appear that there is no compelling evidence suggesting a benefit. Subsets of patients, such as those with hypertension, diabetes, poor left ventricular function or chronic kidney disease, appear to see benefit.

Ivabradine has also been recommended as an additional agent that may be used in the setting of refractory angina, although the addition of ivabradine to standard background therapy to reduce heart rate in patients with stable coronary artery disease without clinical heart failure did not improve patient outcome in the SIGNIFY trial.

Newer agents — ranolazine

Ranolazine has been approved for use in patients with refractory angina. Its method of action was originally thought to be by partial inhibition of fatty acid oxidation, but it was later realised that it had that effect only at serum levels not achieved with usual dosing.

The likely important mechanism for ranolazine is by prevention of calcium overload and subsequent increase in diastolic tension due to inhibition of late inward sodium channels. This sodium channel frequently fails to inactivate in several myocardial disease states, such as ischaemia and hypertrophy, with excess sodium ions entering the myocytes and leading to activation of the sodium/calcium exchanger, thereby giving rise to raised calcium concentrations. Given the normal rapid inaction of the late inward sodium channel in normal myocytes, the drug does not exert any significant effect on the normal myocardium at usual doses, which likely increases its therapeutic window.

The usual initial dose is 500mg twice daily, but this can be up-titrated to 1,000mg twice daily if needed.

The beneficial effect in chronic stable angina has been shown in multiple randomised trials. The MARISA trial showed that treatment with ranolazine alone resulted in a dose-dependent increase in pain-free exercise duration and time to angina. Anginal episodes were significantly decreased with the use of ranolazine in combination with calcium channel blockers in the CARISA trial and when compared with placebo in the ERICA trial. The TERISA trial compared ranolazine versus placebo in patients with diabetes and stable angina. Anginal frequency and use of sublingual nitroglycerin were reduced by the drug.

Complex patients

On balance, the most likely group who might require the introduction of escalating anti-anginal therapy are those patients who have incomplete revascularisation after percutaneous coronary intervention (PCI). Stenting techniques and abilities have evolved rapidly. Left main or complex bifurcations stenting strategies have become commonplace, compared to a decade ago. We have become significantly less dependent on more invasive surgical treatments.

This patient group was evaluated in the RIVER-PCI trial, which randomly assigned patients to ranolazine or placebo after incomplete revascularisation with PCI. Although there was symptomatic improvement, in fact there was no difference in the rate of primary efficacy endpoint, which was a complex composite of time to first occurrence of ischaemic-driven revascularisation or ischaemia-driven hospitalisation.

40 years of angioplasty

Percutaneous therapies have become the gold standard in the treatment of coronary disease. The process has been fine-tuned and 2017 marks and celebrates the 40th anniversary of angioplasty. Relatively primitive balloon angioplasty was followed by early bare metal stents, which subsequently led to drug-eluting stents. The drug-eluting stents in use today are the third- and fourth-generation counterparts of their predecessors that were approved for use in 2002. Drug-eluting stents consist of a metallic alloy frame (most commonly cobalt chromium) coated in a polymer that is covered with a drug, which slowly absorbs into the surrounding tissues over several months. Newer, fully-bioresorbable stents made of a polylactic acid frame are available and promise to dissolve away over several years, returning natural vasomotion to the formerly-diseased vessel. There have been some concerns relating to in-stent re-stenosis that have stalled some of the initial enthusiasm, but work in this area continues.

Since its inception in the late 1970s, there has been no convincing evidence that PCI improves survival compared to medical therapy in patients with ‘stable’ ischaemic heart disease. The COURAGE trial published in 2007 had a major impact on care and treatment. Patients with stable coronary artery disease were randomly assigned to aggressive medical therapy or aggressive medical therapy and PCI with bare metal stenting. All received optimal medical therapy. At median follow-up of 4.6 years, there was no significant difference between the two treatment strategies for the primary end-point of death from any cause and non-fatal myocardial infarction. Notably, patients in the PCI group underwent significantly fewer subsequent revascularisation procedures.

To add to the debate, a 2014 meta-analysis of all-cause mortality in 95 trials with almost 100,000 patients compared one type of coronary revascularisation (CABG or stenting) to another or placebo. Newer generations of drug-eluting stents were associated with a reduced mortality, compared with medical treatment. Other meta-analyses comparing optimal medical therapy to PCI have differing conclusions relating to mortality benefit.

For patients with inadequate anginal symptom control with medical therapy, the addition of PCI has been shown to improve symptom severity and frequency.

Future targets

Future treatment strategies will likely come at the heart from other angles. Stem cell therapy involving the transplantation of bone marrow stem cells has been evaluated as a therapeutic treatment option in patients following myocardial infarction or with ischaemic cardiomyopathies. Studies evaluating patients three months following intramyocardial injection of autologous bone marrow-derived mononuclear cells showed a statistically-significant, albeit modest, improvement in myocardial perfusion compared with placebo. Further extensive investigation is required to evaluate potential efficacy, but also safety.

Conclusion

The medication and interventional techniques available now allow us to invariably get on top of anginal symptoms for most of our stable patients. A step-wise strategy with medication introduction and up-titration should be adopted, and coronary intervention should be considered in patients with ongoing or progressive symptoms. 

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