CCCardiol CroatCardiologia CroaticaCardiol. Croat.1848-543X1848-5448Croatian Cardiac SocietyCC_12(5-6)_226-23010.15836/ccar2017.226Review ArticleOptimal Medical Therapy for Stable Angina PectorisOptimalna medikamentna terapija stabilne angine pektorishttp://orcid.org/0000-0001-5332-391XHeitzlerVjeran NikolićRadna skupina za akutni koronarni sindrom, Hrvatsko kardiološko društvo, HrvatskaWorking Group on Acute Coronary Syndrome, Croatian Cardiac Society, CroatiaAddress for correspondence: Vjeran Nikolić Heitzler, Ksaver 10, HR-10000 Zagreb, Croatia. Phone: +385-98-385-002 / E-mail: vjeran.nikolicheitzler@gmail.com062017125-622623030042017150520172017Croatian Cardiac SocietySUMMARY
The pathomorphological substrate of stable angina pectoris differs significantly from that of unstable angina pectoris. Acute coronary syndrome presents with the clinical picture of unstable angina pectoris and myocardial infarction with or without ST-segment elevation, and the invasive approach through percutaneous coronary intervention or surgical myocardial revascularization with optimal medical therapy is indicated. In contrast, stable angina pectoris develops gradually, and many studies have demonstrated that the long-term results (fatal outcomes) do not differ in comparison with the invasive approach. The main prerequisite is the application of optimal medical therapy. It is based on three medications: extended-release nitrates, beta blockers, and calcium antagonists, in addition to other treatment.
SAŽETAK
Patomorfološki supstrat stabilne angine pektoris uvelike se razlikuje od nestabilne angine pektoris. Akutni koronarni sindrom prezentira se slikom nestabilne angine pektoris, infarkta miokarda s elevacijom ili bez elevacije ST segmenta, a indicirani su invazivni pristup perkutanom koronarnom intevencijom ili kirurškom revaskularizacijom miokarda uz optimalnu medikamentnu terapiju. Za razliku od toga stabilna angina pektoris razvija se postupno i brojna su ispitivanja dokazala da se dugoročni rezultati (smrtni ishodi) ne razlikuju s obzirom na invazivni pristup. Osnovni je preduvjet primjena optimalne medikamentne terapije. U osnovi je čini trijas lijekova: nitrata produženog učinka, beta-blokatora i antagonista kalcija, uz drugu terapiju.
We distinguish between unstable and stable angina pectoris. Unstable angina pectoris is a constitutive part of an acute coronary syndrome with myocardial infarction with or without ST segment elevation. It is most commonly based on the rupture or fissure in atherosclerotic plaque and represents an acute, life-threatening event. It requires relatively rapid emergency intervention in the form of percutaneous coronary intervention (PCI) or cardiac surgery (coronary artery bypass grafting, CABG) (1). In stable angina pectoris, the procedure should be significantly different, since it is a state that usually develops only gradually.
It bears reminding that the prevalence of stable angina pectoris is on the rise and is present in 3% of the population, especially in countries that do not give enough attention to the prevention of risk factors for cardiovascular diseases, including nicotine abuse, untreated or inadequately treated arterial hypertension, hyperlipoproteinemia, diabetes, obesity, and partly also due to lifespan extension and possible family predisposition.
Stable angina pectoris is mostly the consequence of significant atherosclerotic stenosis of coronary arteries, ≥50% constriction of the left main coronary artery or ≥70% stenosis of one or more epicardial coronary arteries. The guidelines of the European Society of Cardiology for the treatment of stable angina pectoris from 2013 (2) introduced a new term in addition to atherosclerotic constriction: microvascular disease and coronary spasm with no significant (≥50%) changes on the great coronary arteries. In men, the disease can manifest as early as the fourth decade of life, whereas it appears later in women; after the age of 60 the incidence of the disease is not associated with the sex.
Data collected from the patient have a key role in establishing the diagnosis of angina pectoris. Patients complain of chest pains, and the feeling of pain can vary individually from pressure to severe pain. In addition to a description of the pain, it is valuable to know whether the pain manifests during exertion. It should be stressed that the extent of the exertion responsible for the appearance of the pain is not constant, which means that the patient can withstand a certain level of exertion on a given day, for instance climbing three flights of stairs, whereas the next day the pain appears already while climbing to the first floor. Why is this the case? If the patient undertakes physical exertion e.g. immediately after a large meal, the pain will manifest earlier, and it can be caused by excitement as well. Symptoms are much more common in winter months, especially when moving to the outside cold from a warm room. Angina pectoris episodes can be very rare, primarily incited only by more severe exertion, but can become a daily occurrence, caused by mild exertion and even happen at rest, which is when the approach to treatment changes and invasive diagnostics are indicated. Stable angina pectoris, as the term itself indicates, has not changed over a longer period, at least for the previous two months. Diagnosis is established by the pain lessening at rest or with nitroglycerin within as little as a few minutes or by typical changes on the electrocardiogram that disappear completely once the pain stops. (2, 3)
The COURAGE (4) study, published in 2007, included 2287 patients in 50 American and Canadian centers with established symptomatic stable coronary heart disease (CHD). Inclusion criteria were proven, at least 70% stenosis in the proximal segment of at least one epicardial coronary artery and patients whose ischemia was objectivized using non-invasive techniques: electrocardiograms, ergometry, etc. Patients were then randomized into two groups. The first group of patients (1149) consisted of patients with optimal medical therapy who underwent PCI, whereas the second group (1138) consisted of patients who were only treated with optimal medical therapy. It is interesting to note that it was this study that introduced the concept of optimal medical therapy to the treatment of stable angina pectoris. Patient follow-up lasted an average of 4.6 years. The cumulative rate of adverse cardiovascular outcomes (death, infarction, and stroke) was 19.0% in patients treated with PCI application and 18.5% in those treated only with optimal medical therapy. There are multiple reasons for this result, but according to the leading experts in this field, the main reason lies in the fact that the coronary artery with its chronic atherosclerotic constriction is usually not the cause of acute coronary events. Lately, we have seen study results which indicate that removing the “critical” atherosclerotic stenosis through PCI application or through cardiac surgery does not always lead to the disappearance of the symptoms. Despite successful revascularization, 25-35% of patients still report pronounced angina pectoris symptoms with positive cardiac stress test. This contributes to new insight in the pathogenesis of angina pectoris and includes many mechanisms with or without atherosclerotic obstruction which can cause myocardial ischemia, and thus angina pectoris as well. The focal or diffuse spasm of the coronary artery with or without atherosclerotic plaques has been mentioned, as well as changes at the level of microcirculation. (5)
There is no doubt that percutaneous coronary intervention represents a superior and irreplaceable form of treatment for acute coronary syndrome. Acute coronary syndrome is the reason for at least 50% of PCI interventions in the United States of America and the world. In these cases, the rule of PCI remains uncontroversial. The researchers in the COURAGE study, as well as other authors over the last few years, report that applying PCI in stable CHD should not be rushed, since identical results can be achieved with optimal medical therapy as well. (6-8)
It is very well known that untreated CHD results in the progression of diseases – angina pectoris, myocardial infarction, congestive left heart failure, and finally death. Although some untreated patients remain asymptomatic or have the symptomatology of chronic stable angina pectoris, they are very likely candidates for sudden cardiac death. (9)
The main treatment goal in patients with stable angina pectoris is to improve quality of life, i.e. ameliorate symptoms, reduce the frequency of angina attacks, slow or stop progression of the disease, and prevent adverse events such as heart attack or death. It has now become known and indubitable that interventional therapy reduces or mostly removes the symptoms, but does not prolong life in comparison with medical therapy.
Interventional treatment (PCI or CABG) for stable angina pectoris is justified in cases of therapeutic refractory angina pectoris, multivessel coronary disease, stenosis (>50%) of the left main coronary artery, significant stenoses and reduced ejection fraction (EF <30%). (10)
Ultimately, the question that needs to be asked is what optimal medical therapy for stable angina pectoris really is? Its basis is the triad of nitrates, beta blockers, and calcium antagonists. This is of course followed by aspirin, ACE inhibitors, or sartans, and other appropriate treatment in cases of comorbidity (arterial hypertension, diabetes, hyperlipoproteinemia, hyperuricemia). Despite these recent recommendations for effective medication combinations, the prevalence of their use is not satisfactory, and many patients with stable angina pectoris remain sub-optimally treated, with the indication for PCI often too easily set. (6) Nitrates need no special mention. Their vasodilatory effects are well known, as is the possibility of the oversaturation of their receptors if they are prescribed too often. Third-generation calcium antagonists based on dihydropyridine, primarily amlodipine and related drugs, selectively block calcium entry into the musculature of the vascular wall, including the coronary arteries, causing vasodilation and a drop in arterial pressure, better cardiac work, and reduced need for myocardial reoxygenation. (11) This is a drug that, unlike verapamil and diltiazem, does not result in the prolongation of atrioventricular conduction and can be combined with beta blockers. Cardioselective beta blockers block the noradrenaline beta-1 adrenergic receptors, reduce heart rate, prolong the diastole, and also reduce arterial pressure values and myocardial oxygen requirements. It follows that the combination of calcium antagonists and beta blockers is more effective than separate application of only one of these drugs. (12)
Aside from the basic triple therapy for stable angina pectoris, ivabradine has its use in patients where sinus activity is above 60/min despite beta blocker treatment, or in those who do not tolerate beta blockers due to hypotensive arterial pressure values or for some other reason. It is recommended to try to combine beta blockers with ivabradine.
As early as 1999, Prof. Lionel Opie wrote in the Lancet medical journal that “...Ischemic disease is mostly considered a consequence of hemodynamic changes. However, in recent years we have realized that ischemic heart disease has an important metabolic component in its pathogenesis, and today we recognize the importance of treating that component as well”. (13) Drugs that effect the metabolic characteristics of the myocardium are trimetazidine and ranolazine. These are drugs that are considered second line medication according to treatment guidelines for stable angina pectoris (2): trimetazidine is in class II b and ranolazine in class II a.
Conclusion
Numerous studies starting with the COURAGE study have shown that the application of medical therapy, i.e. the combination of nitrates, beta blockers, and calcium antagonists, is justified in the treatment of stable angina pectoris. There is long-term evidence that this form of treatment is not inferior in comparison with the application of invasive procedures using PCI and CABG. The question of the extent to which patients are informed on the risks and benefits of invasive treatment is yet to be answered. The prevalence of PCI in the US has not gone down since the publication of the COURAGE study, and most patients are not treated using optimal medical treatment. (14) The situation is not significantly better in Europe, where the ratio of interventions in stable and unstable patients is the same at 50%. (15)
LiteratureHammCWBassandJPAgewallSBaxJBoersmaEBuenoHESC Committee for Practice Guidelines. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). . 2011 Dec;32(23):2999–3054. 10.1093/eurheartj/ehr23621873419Task Force MembersMontalescotGSechtemUAchenbachSAndreottiFArdenCBudajA. 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. . 2013 Oct;34(38):2949–3003. 10.1093/eurheartj/eht29623996286KannelWBFeinleibM. Natural history of angina pectoris in the Framingham study. Prognosis and survival. . 1972 Feb;29(2):154–63. 10.1016/0002-9149(72)90624-85058341BodenWEO’RourkeRATeoKKHartiganPMMaronDJKostukWJCOURAGE Trial Research Group. Optimal medical therapy with or without PCI for stable coronary disease. . 2007 Apr 12;356(15):1503–16. 10.1056/NEJMoa07082917387127HuqiAMarilliM. Understanding and treating angina occuring after angioplasty. . 2016;21:177–88.ChanPSPatelMRKleinLWKroneRJDehmerGJKennedyKAppropriateness of percutaneous coronary intervention. . 2011 Jul 6;306(1):53–61. 10.1001/jama.2011.91621730241MiloMNerlaRTarziaPInfusinoFBattipagliaISestitoACoronary microvascular dysfunction after elective percutaneous coronary intervention: correlation with exercise stress test results. . 2013 Sep 20;168(1):121–5. 10.1016/j.ijcard.2012.09.05923058352Yong AS, Ho M, Shah MG, Ng MK, Fearon WF. Coronary microcirculatory resistance is independent of epicardial stenosis. Circ Cardiovasc Interv. 2012 Feb 1;5(1):103-8, S1-2. https://doi.org/10.1161/CIRCINTERVENTIONS.111.966556DeligonulUVandormaelMGShahYGalanKKernMJChaitmanBR. Prognostic value of early exercise stress testing after successful coronary angioplasty: importance of the degree of revascularization. . 1989 Mar;117(3):509–14. 10.1016/0002-8703(89)90722-92521972SerruysPWMoriceMCKappeteinAPColomboAHolmesDRMackMJSYNTAX Investigators. Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease. . 2009 Mar 5;360(10):961–72. 10.1056/NEJMoa080462619228612Kannam JP, Aroesty JM, Gersh BJ. Stable ischemic heart disease: Overview of care. Available at: https://www.uptodate.com/contents/stable-ischemic-heart-disease-overview-of-care#H8 (29.4.2017).Cruickshank JM. The modern role of beta-blockers in cardiovascular medicine. People’s Medical Publishing House ‡ USA, 2011.OpieLH. Proof that glucose-insulin-potassium provides metabolic protection of ischaemic myocardium? . 1999 Mar 6;353(9155):768–9. 10.1016/S0140-6736(98)00385-710459953Henderson RA, Timmis AD. Almanac 2011: stable coronary artery disease. The national society journals present selected research that has driven recent advances in clinical cardiology. Kardio list. 2011;6(11):271-85. Available at: http://www.kardio.hr/pdf/Kardio%20list_2011_6_11_271-285.pdf (29.4.2017).Strozzi M. Stable angina petoris in Croatia. Kardio list. 2011;6(11):268-70. Available at: http://www.kardio.hr/pdf/Kardio%20list_2011_6_11_268-270.pdf (29.4.2017).