Peculiarities of pharmacotherapy of stable angina in elderly patients

Background

There are two methods of treatment for elderly patients with angina pectoris – medical and surgical. However, a number of studies have indicated that the strategies of revascularisation and aortic coronary shunting are used less frequently when compared to the strategy of pharmacotherapy for stable coronary artery disease (SCAD). The TIME [1] and COURAGE [2] studies indicated the absence of a long-term survival effect from an initial strategy of treatment (surgical [percutaneous coronary intervention (PCI)] against medical). In the BARI 2D study [3], which investigated the optimal treatment strategy for SCAD with comorbid type 2 diabetes mellitus, no significant difference was found concerning the morbidity rate in relation to the treatment strategy (medical, PCI, type of insulin therapy). In addition, the frequency of restenosis and complications among patients older than 80 years is higher than among younger patients: strokes are found more often after aortal coronary shunting than after stenting of the coronary arteries, and five-year survival time among octogenarians is 86% after aortal coronary shunting and 81.4% after stenting.

Considering all the above-mentioned specificities, the main approach in the treatment of elderly patients with angina pectoris remains the medical one (which is mandatory irrespective of whether revascularisation is performed or not). This is based on such principles as the evidenced primary efficacy and reasonability of medical therapy as presented in the recommendations of ESC 2013 [4] and in the NICE guidelines [5] concerning the treatment of stable angina, strategies for the management of geriatric patients and individualised clinical pharmacology of medicines administered.

How do we find the right balance between complying with recommendations to treat patients with angina and pharmacotherapy in the elderly? The answer to this question might be found by applying the principles of individualised pharmacotherapy, taking into account the clinical and pharmacological specificities of all of the drugs used as well as the various possible combinations.

Drugs that improve survival

Drugs which improve survival are aimed at improving prognosis (by preventing myocardial infarction and death).

Antiplatelet drugs

Low-dose acetylsalicylic acid (aspirin) daily is recommended for all SCAD patients; clopidogrel is indicated as an alternative in the case of aspirin intolerance [4].

Elderly patients have a high cardiovascular risk and aspirin can be used in a positive fashion here. Indefinite, regular use of acetylsalicylic acid in patients with stenocardia reduces the risk of developing recurring myocardial infarction (MI) by an average of 23%. Clopidogrel, the role of which has been proven in such trials as CURE [6], CAPRIE [7], CLASSICS [8], CREDO [9], CARESS [10], CCS-2 [11], MATCH [12 ], WATCH [13], CHARISMA [14], CASPAR [15], is not inferior to aspirin in the prevention of acute vascular events and, by achieving positive results as a secondary prophylaxis, may even be superior to it [16]. In spite of the obvious benefit of antiplatelets in the treatment of stable angina, it should be noted that there are some difficulties in administering them to the elderly.

A dose of acetylsalicylic acid must be seen to be minimally effective in order to provide a balance between its therapeutic benefit and any possible gastrointestinal side effects. Therefore, any decision about aspirin use in the treatment of elderly patients with stable angina should be made on an individual basis. A recommended optimal dose range is between 75 and 150 mg per day. According to expert opinion, before the prescription of aspirin for elderly patients, an estimation of the risk of gastrointestinal bleeding must be made, even considering the use of gastroscopy.

Despite the proven advantages of clopidogrel, the clinical use of this drug in the treatment of stable angina in elderly patients remains relatively limited. This is related to the absence of recommendations on the dosing regimen of clopidogrel for the elderly due to the possible changes in the metabolic processes involved and their influence on the pharmacokinetics of this agent.

β-blockers

β-blockers have achieved a 30% risk reduction for cardiovascular (CV) death and MI. Thus, β-blockers may also be protective in patients with SCAD, but there is no supporting evidence from placebo-controlled clinical trials. First-line treatment is indicated with β-blockers in order to control heart rate and symptoms.

β-blockers reliably decrease the probability of sudden cardiac death and recurrent MI. They also improve life expectancy in SCAD complicated by heart failure (HF). The choice of a β-blocker (i.e., bisoprolol, slow-release metoprolol, nebivolol, carvedilol) should be made on available evidence-based data from major clinical trials.

However, it is only possible to expect these preparations to be effective during the course of stable angina when the distinct effect of β-receptor blockade is produced. For this purpose, it is necessary to control the resting heart rate within the strict limits of 55-60 beats per min. By observing this principle, β-blockers can certainly diminish the frequency and duration of "silent" and painful episodes of myocardial ischaemia in stable angina.

In a number of clinical trials, the high efficiency and good tolerance of β-blockers have been shown in elderly patients. At the same time, the majority of them included only patients with concomitant hypertension (SHEP [17], STOP Hypertension [18]) or heart failure (SENIORS [19]). Given a background of long-lasting use of β-blockers in the elderly, when a decrease in blood pressure of 20/8 mmHg was reached, a reduction in the number of strokes of 47%, a reliable decline of in the general death rate of 43% and a decrease in the level of cardiac complications of 40% were shown.

According to national data registries, only one-third of patients older than 75 years receive β-blockers and, among patients older than 85 years, this falls to only one quarter. Such a situation resulted in a special analysis of the clinical course of stable angina that was conducted in elderly patients concerning the presence of β-blockers in their treatment.

Data from this analysis conducted in our geriatric clinic showed that the success rate in the prescription of β-blockers for permanent use in stable angina patients was only 17%. Important contraindications for β-blocker use in the case of our geriatric clinic included the following: severe bronchial obstruction due to bronchial asthma or COPD IV, atrioventricular block; or the occurrence of intolerance to their long-lasting use (9%), the decline of arterial blood pressure (2%), bradycardia less than 55 bpm (2%), and increase in the frequency of episodes of dyspnoea and dizziness (5%).

Thus, in prescribing β-blockers for the elderly, the control both of management (changes of clinical symptoms of stenocardia, heart rate and blood pressure [BP] levels, ECG recording at rest and cardiac ultrasound investigation) and of any encountered side effects is required. Also, in this category of patients, high-dose β-blockers must be ruled out because of a greater frequency in the development of congestive heart failure and acute heart failure, the appearance of blockades of different localisation, and the dysfunction of SA and AV nodes.

Statins

Statins are recommended in all SCAD patients. However, data from the Framingham study showed that with increasing age the correlation between the risk of the development of cardiovascular events and the level of total cholesterol (TC) and LDL-cholesterol decreases becoming ambiguous in the group of patients between 65 and 94 years of age [20].

At the same time, the benefit of statins in the prophylaxis of cardiovascular events is higher in the elderly as compared to younger patients because of an increased risk of complications in this age group. Data from an additional analysis of the Heart Protection Study (HPS) [21] show that indefinite treatment with simvastatin has effective results in terms of a decline in the different cardiac outcomes in the group of patients older than 75 years. In a Scandinavian study [22], a reduction of death after MI and sudden cardiac death of 34% was shown in the subgroup of patients older than 65 years of age with the long-lasting use of statins. The results of another study, 4S [23], demonstrated a high level of safety of statin management in the long term: the frequency of hepatic enzyme activation in a group with statin use did not exceed analogous indices in a control group.

In the SAGE study, the use of high doses of atorvastatin resulted in a decline of LDL levels in a group of elderly people (with a mean age of 72 years) of 55%. [24]. This research simply proved that, among elderly people with stable angina, intensive statin therapy resulted in a decline of levels of cholesterol and a substantial decrease in the rate of CV death. In the PROSPER randomised trial [25], it was proven that a 40 mg daily dose of pravastatin in the elderly (70-82 years) during a 3.2-year observational period decreased the frequency of nonfatal MI by 19% and the risk of death in the course of ischaemic heart disease by 24%. In addition, this research demonstrated a good tolerance of statin use in the elderly: no cases of myopathy, liver dysfunction, statistically reliable changes of memory worsening and dementia were recorded. Thus, statins have been proven to reduce the risk of the development of coronary events in the elderly and therefore their administration is obligatory in the treatment of elderly patients with stable angina [4].

The main contraindications to statin use are severe liver diseases, known skeletal muscle problems, and established previous individual intolerance to statin preparations.

Drugs which block the renin-angiotensin system

Angiotensin-converting enzyme inhibitors (ACE-i) (or angiotensin II receptor blockers [ARBs] in the case of ACE-i intolerance) are recommended in the presence of concomitant conditions (e.g., heart remodelling, MI in anamnesis, heart failure, hypertension or diabetes).

The efficacy of ACE-i administration for patients with ischaemic heart disease (IHD) has been proven in several trials. For example, in the HOPE study in patients with IHD and at high risk of cardiovascular complications, after the use of ramipril (10 mg daily) a reduction of the general rate of urgent acute cardiovascular events, general and cardiovascular mortality and the need for myocardial revascularisation was seen [26]. In the large EUROPA study, the treatment of patients with IHD (without clinical signs of chronic heart failure) with perindopril at a daily dose of 8 mg reliably reduced the risk of cardiovascular mortality, the frequency of nonfatal MI and sinus arrest, and decreased the rate of development of HF [27].

In contrast, other trials, where the relevant positive clinical effect of the use of ACE-i was based on the origin of the cardiovascular complications, namely QUIET [28] and PEACE [29], where quinapril and trandolapril were used, did not prove the efficiency of these medicines on the course of chronic IHD or on the development of cardiovascular complications. Evidently, the prophylactic activity on the course of IHD is inherent only to some specific members of the ACE-i group but not to all of them. For these reasons, the general recommendations for the use of ACE-i in patients with stable angina must be based on the presence in the clinical status of concomitant hypertension, diabetes mellitus, heart failure, proven remodelling of the left ventricle or previous MI. In the case of absence of the above-mentioned, it is recommended to take into account the expected benefit of treatment, the risk of negative outcomes, and the costs of the treatment, including side effects [30].

Of course, in the case of drug intolerance, ACE-i can be substituted by ARBs, with preference to three – candesartan, valsartan and telmisartan – on the basis of evidence-based medicine.

The experience of the use of ARBs allows us to conclude that drugs from this group typically show high clinical efficiency, a low level of side effects distinct from other classes of medicine which are prescribed for the elderly, the possibility of protective activity on target organs and a decline of morbidity and mortality. Of note also is the high adherence of patients to the course of treatment because of the comfortable dose regimen [31].

Drugs which improve quality of life

Calcium channel blockers

Until now, there are insufficient data to prove the beneficial influence of Ca-blockers in the prognosis of the elderly with stable angina, although the drugs that decrease heart rate such as verapamil are proposed as alternatives if β-blockers are not tolerated in patients with previous MI and absence of left ventricular (LV) dysfunction. Fundamental pharmacology shows that both groups have antianginal activity - dihydropyridines (nifedipine, amlodipine, felodipine and others) and non-dihydropyridines (verapamil and diltiazem). These drugs are widely used for stable angina in the elderly, because they reduce the rate of episodes of stenocardia and increase the tolerance to exertion, and lead to improvement in the quality of life [32].

Moreover, in the treatment results of variant stenocardia in the elderly, calcium channel blockers exceed nitrates and β-blockers. The pharmacological features of amlodipine compared to other dihydropyridines defined its preferential benefit on the development of cardiovascular complications. In particular, for elderly patients, the special indication for prescription of this drug is the combination of hypertension and IHD in a patient. After sub-analysis of the CRUCIAL trial with a proactive multi factorial intervention strategy based on single-pill amlodipine/atorvastatin [SPAA], a treatment-related reduction in the calculated Framingham 10-year CV risk in patients ≥65 years was observed [16]. Therefore, the use of amlodipine reliably reduces the number of ischaemic episodes including “silent ischaemia” in the course of stable angina in the elderly and increases the tolerance to physical exertion.

Ca-blockers are more often recommended as the second drug in the combined management of stable angina, predominantly with a previously prescribed β-blocker. In a series of placebo-controlled studies, the efficacy of such types of drug combinations was proven. With the administration of long-acting dihydropyridines, Ca-blockers in the dose diapason of 10-20 mg one or two times per day based on β-blocker use decrease the frequency of episodes of pain and myocardial ischaemia according to Holter monitoring data. Of course, when prescribing Ca-blockers in the elderly, the appearance of peripheral oedema, arterial hypotension, and constipation should be monitored. Non-dihydropyridine Ca-blockers in combination with β-blockers are contraindicated.

Nitrates

Short-acting nitrates are recommended. Currently, three drugs from this group are used - nitroglycerine, isosorbide dinitrate and isosorbide-5-mononitrate.

Administration of nitrates is often associated with a marked reduction of arterial pressure and changes of vascular reactions (both veins and arteries) in the cerebral circulation; therefore, elderly patients when taking nitrates often develop headaches and ortostatical hypotension. The recommendation, in this case, is that, when taking nitroglycerin in case of angina pectoris, the patient should sit down and not lie down. In this group, preference among nitrates should be given to preparations of isosorbide-5-dinitrate that can maintain their effect during the day, with a lack of action of the nitrate at night (to prevent the development of tolerance).

In 27 randomised controlled trials (RCTs), 12 different comparisons of three different nitrates (nitroglycerin, isosorbide dinitrate and nicorandil) were reported. There was no difference in the primary outcome of all-cause mortality, acute myocardial infarction, acute heart failure, cardiac arrhythmia or cardiac arrest in any of the comparisons [33].

Thus, nitrates do not improve the outcomes of stable angina with long-term use; therefore, they should not be prescribed in the absence of symptoms of retrosternal pain and myocardial ischaemia. Adverse events are reported in a heterogeneous way. The participants treated with nitrates have hypotension, tachycardia and headaches with no statistically significant differences among the different nitrates. In addition, nitrates should not be administered together with sildenafil due to possible serious complications. After taking sildenafil, patients should not take nitrates within 24 hours [34].

Cardioprotectors

Cardioprotectors are recommended as second-line treatment. Trimetazidine may be considered.

In the TRIMPOL-I study, 700 patients with a positive physical exertional test without a significant effect of the treatment of long-acting nitrates or calcium antagonists, adding trimetazidine (slow release) resulted in a statistically significant decrease in the frequency of angina attacks [35]. In the Russian study TRIMER (Trimetazidine in Elderly People), in which  patients with stable angina functional class II-III in the age range of 65-80 years old were included, three-month treatment with trimetazidine reduced the frequency of angina attacks, reduced the frequency of ST segment depression on ECG, and contributed to the positive dynamics of the indicators of quality of life [36].

Trimetazidine is used as a complementary therapy added to standard antianginal drug therapy.

Others (ivabradine, nicorandil, ranolazine)

The underlying cause of angina pectoris is usually macrovascular SCAD, but may be microvascular in elderly people [4]. For second-line treatment, it is recommended to add long-acting nitrates or ivabradine, nicorandil or ranolazine according to heart rate, blood pressure and tolerance.

Ivabradine in patients with stable angina and a heart rate ≥70 bpm, along with the anti-ischaemic effect, reliably reduces the risk of MI (36.0%) and the need for revascularisation (30.0%). It can be used both independently and in combination with β-blockers. Due to the fact that, in contrast to β-blockers, ivabradine maintains coronary vasodilation and a positive inotropic effect, leading to tolerance for exercise stress tests with a decrease in heart rates greater than seen when taking β-blockers.

In the large IONA (Impact Of Nicorandil in Angina) study, it was proven that regular antianginal therapy with nicorandil had significant efficacy on the prognosis of stable stenocardia. It was shown that the addition of nicorandil resulted in a significant reduction in the mortality rates of patients with stable angina [37].

Ranolazine is a second-line antianginal drug approved for use in people with stable angina. However, the effects of ranolazine for people with angina are considered to be modest, with uncertain clinical relevance. Ranolazine has been shown to improve exercise tolerance test (ETT) parameters and angina frequency without substantial haemodynamic effect [38]. However, ranolazine has also been related to prolongation of the QTc interval, although not pro-arrhythmic at therapeutic doses [39]. Moreover, ranolazine has been shown to have antiarrhythmic effects by reducing atrial and ventricular arrhythmias [40]. Older patients need a strict assessment of QT interval duration in the administration of ranolazine, as well as when used with other drugs causing prolongation of QT [41].

In general, the strategy of treatment assumes mandatory use of a preventive combination for all patients (statin + acetylsalicylic acid) with a medical effect on the degree of myocardial ischaemia: a short-acting nitrate in combination with a β-blocker or non-dihydropyridine calcium antagonist, or, in case of necessity, a combination of β-blocker with dihydropyridine Ca-blockers. In case of ineffectiveness or intolerance to any of the drugs, alternative pharmacotherapy is suggested assuming administration of monotherapy with second choice drugs (nitrates of a prolonged action, ivabradine or nicorandil), or a combination of a β-blocker with any of the second choice drugs and, finally, when there is no control, administration of three antianginal basic drugs. In addition, under conditions of structural changes in the myocardium or MI in anamnesis, preventive pharmacotherapy is suggested with the administration of ACE-i or ARBs. In general, antianginal therapy is considered effective if it is possible to eliminate episodes of stenocardia completely or to reduce the functional class of the patient from a higher to a lower class (I) while maintaining a good quality of life.

Therefore, elderly people should be treated in a similar manner to patients with a mild form of chronic kidney disease. Reduced kidney function results in an increased concentration of drugs excreted as unchanged, active or toxic metabolites. Moreover, t1/2 becomes longer, creating the danger of an accumulation of drugs, their over dosage and increasing the risk of side effects, especially in case of regular intake of drugs.

Conclusion

Table 1. Summary of pharmacological treatments recommended in patients with stable angina aged >65 years [4,42].

AUC: Area under the plasma drug concentration versus time curve; Cmax: maximum serum concentration; t1/2: half-life

Analysing the number of drugs administered, it seems obvious that almost every patient receives a minimum of four drugs, and a maximum of up to eight drugs from different groups, and this only in case of stable angina pectoris in its chronic course when there are no other cardiovascular complications or comorbid pathologies. If these complex conditions exist they would require separate pharmacotherapy, dealing with the issues of polytherapy (polypharmacy) and drug interaction, compliance and adherence.

In conclusion, a rational choice of the optimal number and types of drugs for the treatment of stable angina pectoris requires understanding the individualised age-related specifics for each of these agents including some pharmacokinetic and pharmacodynamic interactions – in order to prescribe what is effective and safe pharmacotherapy for elderly patients. It should always be remembered that the efficacy and safety of drugs used in the elderly depend on a wide range of factors which manifest themselves in a different fashion for each individual elderly patient and thus require close attention by the clinician.