Information released by our government in 2008 shows that there are 160 million elderly people (≥ 60 years old) in China. With the aging of China’s population, the incidence and death rate of cardiovascular diseases are increasing year by year, and coronary heart disease is one of the major killers. The results of our WHO Global Burden of Disease Study predicts that the number of deaths from cardiovascular disease in China will reach 4 million/year in 2020. There is no major difference between the types and principles of drug therapy for elderly patients with coronary heart disease and non-elderly patients, but there are application characteristics for elderly patients when it comes to each drug specifically.
I. Nitrates.
Nitrates include: nitroglycerin (NTG), isosorbide dinitrate (ISDN), isosorbide 5-mononitrate (ISMN) and pentaerythritol tetranitrate (PT), and erythritol tetranitrate (ET), the first three of which are widely used in clinical practice. The pharmacokinetic characteristics of the different nitrates are significantly different.
NTG is the representative drug of nitrate. It is characterized by its unstable nature, volatile, flammable and explosive, strong first pass clearance effect in the liver and oral bioavailability less than 10%, therefore, it is not suitable for oral administration. NTG has a short half-life of only a few minutes, and the blood concentration decreases rapidly within 20-40 minutes after stopping the intravenous drip or removing the transdermal patch, and the NTG is metabolized in the vascular wall, and the uptake of NTG by the venous vessels is significantly stronger than that of the arteries. NTG sublingual tablets are unstable and should be used within the expiration date.
ISDN has become the most widely used long-acting nitrate since its introduction in 1947, with a significantly lower first pass clearance effect in the liver than NTG. -The latter has a half-life of 4-6 hours and exerts a major subsequent prolonged pharmacological effect (50-60%), while the former is less active and has little practical clinical significance.
ISMN is a new generation of long-acting nitrate developed late and used clinically since 1978, with no first pass clearance effect by the liver after oral administration and a bioavailability of nearly 100%. The parent drug exerts its pharmacological properties directly without hepatic metabolism and has a half-life of 4-5 hours.
Elderly people apply sublingual NTG and intravenous nitrates, especially the old elderly patients, should be taken in a flat position or sitting position before taking to avoid the occurrence of postural hypotension, some patients can induce vagal reflex leading to profuse sweating, pay attention to blood volume replenishment. There are many elderly patients who take long-acting nitrates orally can lead to low blood pressure throughout the day, and treatment should be individualized and switched to patches. There is little clinical evidence addressing the prognosis of nitrates for coronary artery disease in the elderly.
II. β-blockers.
Beta-blockers, such as betalactam and bisoprolol, mainly reduce myocardial oxygen consumption and improve exercise tolerance, thus improving angina pectoris. They are a large class of drugs used very widely in clinical practice, with a wide range of indications, and play an important role in the treatment of hypertension, arrhythmias, coronary artery disease, heart failure and other diseases. However, in elderly patients, its utilization rate in the overall population is low due to various concerns, and its application dose is also low compared to the recommendation of foreign guidelines. In a 2006 survey of primary care physicians in China, the use of beta-blockers in patients with chronic heart failure was only 40.0%, and the target dose was only 1.0%. In a survey conducted in a large tertiary care hospital, the rate of beta-blocker use in outpatients with heart failure could reach 77.5%, but only 2.5% reached the target dose.
(A) Clinical application of β-blockers
1.Chronic stable coronary artery disease
Indications: Beta blockers are the cornerstone of treatment of stable coronary artery disease to control myocardial ischemia, prevent MI and improve survival, regardless of prior history of MI (Class I recommendation, Level of Evidence B). Beta blockers should be preferred in patients with chronic angina or myocardial ischemia with hypertension, prior MI, or left ventricular hypoperfusion (Class I recommendation, Level of Evidence A).
Type and dose: β1 receptor blockers are clinically preferred and commonly used metoprolol, atenolol, and bisoprolol. Non-β1 receptor selective ones with many adverse effects are largely not used. Beta blockers should be started at small doses (e.g. 1/4 target dose), and if tolerated can be gradually increased to the target dose. In principle, it is appropriate to bring the resting heart rate down to the ideal level (55-60 beats/min). The dose should be individualized and can be adjusted at any time according to symptoms, heart rate and blood pressure.
Caution: Special care should be taken to reduce or temporarily discontinue the dose if symptomatic severe bradycardia (heart rate below 50 beats/min) develops after dosing, rather than discontinuing the drug, as this may lead to a rebound increase in heart rate and risk of frequent myocardial ischemia or angina symptoms.
Two early large clinical trials (ISIS-1 and MIAMI), as well as large clinical studies such as TIMI-II, National MI Registry 2, GUSTO-I, PAMI, and CADILLAC after the widespread use of reperfusion therapy in AMI, have confirmed that beta blockers given orally or intravenously reduce acute mortality and improve long-term prognosis in AMI. The recently published COMMIT/CCS-2 trial is the largest clinical study of beta blockers in AMI to date, with 4 weeks. The primary endpoint event (death, reinfarction, or cardiac arrest) did not differ between the metoprolol and placebo groups; intravenous metoprolol reduced all types of reinfarction and decreased the risk of fatal arrhythmias and ventricular fibrillation, but increased the risk of cardiogenic shock. 2013 ACCF/AHA STEMI guidelines recommend the following: (1) Oral: Start with a small dose and increase gradually to reach a tolerable maximum dose and maintain it. (2) Intravenous administration: metoprolol 25-50 mg every 6 to 12 hours, titrated to a once-a-day extended-release formulation of metoprolol or a twice-a-day regular formulation; carvedilol 6.25 mg twice daily, titrated to the maximum tolerated dose (2) Intravenous administration: metoprolol 5 mg for the first dose slowly (5 to 10 min), repeated once after 5 min if needed If needed, repeat 1 time after 5 min, for a total of 3 times. Other intravenous preparations can also be used, but there is less experience: esmolol first dose 0.25 mg/kg slowly (5-10 min), maintained at 0.025-0.15 mg?kg-1?min-1 if necessary; labetalol 5-10 mg intravenously (3-5 min), maintained at 1-3 mg/min if necessary. Oral β-blockers should be maintained after intravenous administration.
(B) Absolute contraindications to β-blockers mainly include.
Co-contraindications: atrioventricular block of degree II type II and above, excluding bundle branch block; bronchial asthma; acute heart failure attackers, especially with low blood pressure and pre-cardiogenic shock.
Contraindications to β-blockers in ACS are: clinical manifestations of HF (e.g., Killip ≥ grade II), with low cardiac output states such as poor peripheral circulation perfusion, with a high risk of cardiogenic shock (including age > 70 years, basal systolic blood pressure < 110 mmHg, heart rate > 110 beats/min, etc.), and second- and third-degree AV block. Beta blockers should also be used with caution in patients with severe COPD or asthma and a basal heart rate <60 beats/min.
(C) The need for beta-blockers in elderly patients with heart disease
In the treatment of coronary heart disease, β-blockers can slow down heart rate, reduce myocardial contractility, lower blood pressure, and thus reduce myocardial oxygen consumption, as well as reduce heart rate both at rest and after exercise. Studies have shown a 30% reduction in mortality with application in post-infarction patients, but the evidence for improved prognosis in patients with chronic stable angina is not very strong. Therefore, in the 2012 ACCF/AHA guidelines on the diagnosis and treatment of chronic ischemic heart disease, it is stated that Class I recommendations include post-infarction EF ≤ 40%, and normal post-infarction left ventricular function is recommended for 3 years, and longer-term applications are not recommended. And for other types of coronary artery disease is only a Class IIb recommendation.
(iv) Clinicians’ concerns about the use of β-blockers in elderly patients
In elderly patients, clinicians often have various concerns about the use of β-blockers due to the reduced function of the body and the combination of multiple diseases. First of all, the heart rate problem, due to the degenerative changes of sinus node, atrioventricular node and cardiac conduction system in elderly patients, the incidence of morbid sinus node syndrome is relatively high, so clinicians often worry whether the use of drugs will appear after the slow heart rate, cardiac arrest and serious conduction block, and even the development of As syndrome, our hospital in the actual clinical application found in the elderly, especially the old elderly patients have taken amiloride heart 3.125mg heart rate decreased from 60 beats/min to 35 beats/min in some cases. Therefore, we recommend that elderly patients should start with a low dose, or even a minimal dose.
In the CIBIS III study, 1010 patients with mild-to-moderate heart failure were enrolled, all greater than or equal to 65 years old, with a mean age of 72 years, which meets the definition of the elderly population. The target dose of bisoprolol in the regimen was 10 mg/day, and it was observed that 65% of the patients could reach the target dose of 10 mg and 82% could reach the dose of 5 mg and above, indicating that the drug was tolerated more than expected in elderly patients.The COLA II study also showed that carvedilol was well tolerated in elderly heart failure patients >70 years of age, with an overall tolerance of 80%, and that it was well tolerated in patients >80 years of age. The overall tolerability of carvedilol in patients >80 years of age was 80%, and the tolerability in patients >80 years of age was still 76.8%. We performed ambulatory electrocardiograms in 149 elderly patients over 80 years of age and found that their mean heart rate was 68.9±8.4 beats/min, which was within the normal heart rate range. In fact, the need for hospitalization due to severe bradycardia and syncope caused by the application of β-blockers is rarely encountered in clinical practice.
Early trials have shown that beta-blocker use may have adverse effects on glucolipid metabolism, such as increasing the incidence of new-onset diabetes, aggravating dyslipidemia, and masking hypoglycemic symptoms. However, recent studies have shown that carvedilol, which has a vasodilatory effect, has a neutral or positive effect on dyslipidemia and insulin resistance. In patients with definite type I diabetes, non-selective β-blockers can mask hypoglycemic effects, such as tremor and tachycardia, when selective β1-blockers should be used.
For patients with COPD, β-blockers are not a contraindication. COPD often coexists with heart failure or coronary artery disease, and epidemiological surveys show that 37% of deaths in COPD patients are due to cardiovascular disease, which exceeds the proportion of respiratory failure. For patients with COPD combined with coronary heart disease, the application of selective beta1 receptor blockers such as metoprolol and bisoprolol can also reduce mortality, and some studies have shown no significant difference for pulmonary function indicators such as FEV1 relative to placebo. However, some patients have COPD in combination with asthma, which is sometimes difficult to identify clinically, so application needs to start with a small dose and take longer when the dose is adjusted upwards, and changes in dyspnea symptoms need to be monitored. Carvedilol should not be used in such patients.
(E) How to better use β-blockers in elderly patients
All patients have individual differences in tolerance to β-blockers, and generally start with a small dose and gradually adjust the dose upward according to the tolerance. In elderly patients with chronic heart failure, especially in cardiac function class III or IV, their doses are increased more cautiously. To avoid excessive reduction of heart rate, patients should be reminded to monitor their resting heart rate, i.e., the heart rate should not be less than 55 beats per minute when they wake up in the early morning. Some elderly patients who develop severe bradycardia or conduction block with the application of small doses of beta-blockers may themselves have an underlying degeneration of conduction system function, and if beta-blocker therapy is indeed required, it may be considered after the installation of a pacemaker. In patients receiving long-term β-blocker therapy, their dose needs to be adjusted in a timely manner, and the dose should not be increased to achieve the target dose. When slow heart rate or low blood pressure is found, the dose can be temporarily reduced for observation, and sudden discontinuation should be avoided to avoid withdrawal syndrome. Our practice is to first reduce the original dose by half, and after 2 days, when the heart rate and blood pressure do not rebound significantly, if necessary, the dose can be further reduced by half or completely stopped when it is already a small dose. In fact, in patients who have been taking beta-blockers for a long time and have severe slow arrhythmias or hypotension, complete discontinuation of beta-blockers is also the usual measure taken, and no serious rebound has been found so far.
Third, calcium antagonists.
The role of coronary arteries is mainly to make vascular smooth muscle and coronary artery dilation, increase coronary blood flow and anti-coronary artery spasm. nifedipine controlled-release tablets in the hypertensive subgroup of the ACTION study improved endothelium-dependent vasodilatory capacity. the results of both NORMAUSE and CAMELOT studies showed that CCB can stabilize and reverse coronary plaque. The cumulative cardiovascular event rate was reduced. To date, however, there are no direct large-scale clinical studies on the efficacy and safety of CCB (long-acting) applied in ACS. There is little evidence for the use of interrogative medicine in elderly patients with coronary artery disease. The clinical status of calcium antagonists either non-dihydropyridine CCB or dihydropyridine CCB for the treatment of unstable angina due to coronary spasm has been established: however, not all indications for the use of CCB in patients with ACS have been established. In order to avoid or minimize the side effects of calcium antagonists and to avoid as much as possible the use of calcium antagonists in ST-segment elevation myocardial infarction, appropriate selection of indications and rational application in the treatment of unstable angina and non-ST-segment elevation myocardial infarction (for details, see in the sections on unstable angina, non-ST-segment elevation myocardial infarction and variant angina).
(a) Hersinol is indicated for the treatment of: angina pectoris and exertional angina due to coronary artery spasm
(ii) Contraindications.
1.Patients with pathological sinus node syndrome without pacemaker.
2. Second or third degree AV block without a pacemaker.
3.Systolic blood pressure below 12kPa (90mmHg).
4.Patients who are allergic to this product.
5.Patients with acute myocardial infarction or pulmonary congestion.
(C) Precautions for elderly patients: No clinical data on the use of drugs in the elderly have been found, but it is recommended that elderly patients can start with half the usual dose for normal people.
(D) Drug interactions.
1. β-blockers: Studies have shown that diltiazem hydrochloride is well tolerated in combination with β-blockers, but there is insufficient information in patients with left ventricular insufficiency and conduction dysfunction. This product can increase the bioavailability of propranolol by nearly 50%, so the propranolol dose needs to be adjusted when starting or stopping the combination of the two drugs.
2. Cimetidine: Inhibition of cytochrome P450 oxidase affects the first-pass metabolism of this product, which can significantly increase the peak blood concentration of this product and the area under the drug-time curve. Ranitidine only slightly increased the blood concentration of this product.
3.Digoxin: It has been reported that digoxin blood concentration can be increased by 20%, but there are also reports of no effect. Although the results are contradictory, digoxin blood concentration should be monitored when starting, adjusting and stopping the treatment of digoxin to avoid overdose or underdose of digoxin.
4.Anesthetics: They inhibit myocardial contraction, conduction and autoregulation, and have vasodilatory effects, which can have synergistic effects with this product. Therefore, the dose must be carefully adjusted when the two drugs are used together.
IV. Trimetazidine.
Trimetazidine improves myocardial energy metabolism mainly by inhibiting free fatty acid metabolism and increasing glucose metabolism. Free fatty acids and glucose are the main energy supply substances of myocardium, and the oxygen consumption of free fatty acid oxidation to produce equal amount of ATP is higher than that of glucose oxidation, and the rate of glucose oxidation can be significantly inhibited by excessive oxidation of free fatty acids. Therefore, inhibition of free fatty acid oxidation and enhancement of myocardial glucose metabolism are beneficial to improve cellular damage and myocardial function caused by myocardial ischemia. This product can reduce free fatty acid metabolism, thus allowing the myocardium to produce myocardial energy supply mainly by glucose metabolism. In addition, it decreases free fatty acid metabolism to produce ethyl phthalate coenzyme A, which stimulates pyruvate dehydrogenase and indirectly enhances glucose oxidation. The current guideline recommendation is that it can be used in patients with stable coronary artery disease (II A)
On June 22, 2012, the European Medicines Agency (EMA) issued a message recommending restriction of trimetazidine use. The EMA recently completed an evaluation of the safety and efficacy of trimetazidine, with particular attention to the evaluation of the efficacy of trimetazidine and the reports received of adverse events causing parkinsonism. The EU Committee for Medicinal Products for Human Use (CHMP) concluded that
1. For patients with angina pectoris, the clinical benefits of trimetazidine still outweigh the risks. However, its use is restricted to patients who are intolerant to other angina medications or whose angina is not controlled by other methods.
2. In patients with tinnitus, vertigo, and visual field disturbances, there is insufficient evidence of trimetazidine’s effectiveness. Therefore, the CHMP recommends that trimetazidine no longer be used for this indication.
3. Based on current data, trimetazidine may lead to a risk of motor dysfunction, such as Parkinson’s syndrome. Therefore, CHMP recommends that a warning message should be added to the drug insert: Warn healthcare professionals and patients about the risk of motor dysfunction, such as Parkinson’s syndrome, that may result from taking trimetazidine. And add contraindications: contraindicated in patients with Parkinson’s syndrome or patients with symptoms similar to Parkinson’s syndrome, and contraindicated in patients with severe renal dysfunction.
V. Statins.
In recent years, with the publication of the results of several large-scale clinical trials of statins for lipid-regulating therapy, statins are considered safe and effective lipid-regulating drugs and have become a recommended treatment in national guidelines for the prevention and treatment of cardiovascular diseases. Because most of the I clinical trials were completed in carefully screened patients under 70 years of age with cardiovascular disease and high risk, clinicians have doubts about whether the elderly population, especially the elderly, can benefit equally from statins and the safety of long-term treatment, and the prescription rate of statins for the elderly is low, and less than half of the elderly with indications for statins are used.
(A) Pooled analysis of statin use in elderly patients.
Statins for Secondary Prevention in Elderly Patients is a meta-analysis of the application of statins for secondary prevention in elderly patients. 19,569 patients aged 65 to 82 years with coronary heart disease from nine clinical trials (4S, CARE, LIPID, HPS, PLAC I, REGRESS, nARE, uPs, PROSPER) in recent years were pooled and analyzed, and the results showed that statin treatment group with all-cause mortality of 15. 6% and the placebo group with 18.7%; resulting in a 22% reduction in relative risk (RR 0.78, 95% confidence interval, 0.65-0.89). Also, statins reduced the morbidity and mortality of coronary heart disease by 30% (RR 0.70; 95% confidence interval, 0.53-0.83), nonfatal myocardial infarction by 26% (RR 0.74; 95% confidence interval, 0.60-0.89), hemodynamic reconstruction by 30%, and stroke by 25%. One person was saved per 28 cases treated, showing a greater benefit than in past pooled analyses (1 person saved per 6l cases treated).
One of the PROSPER studies is a lipid-lowering trial for the elderly population: Prospective study of pravastatin in the elderly at risk (PROSPER): 5804 patients (2804 men, 3000 women) aged 70 to 82 years with a history of vascular disease or cardiovascular risk factors were randomized to pravastatin 40 mg/d or placebo with a mean 3.2 years of follow-up. The results showed a 34% reduction in LDL-C, a 15% reduction in composite clinical endpoint events, a 19% reduction in nonfatal myocardial infarction and coronary death, and no difference in stroke or all-cause death in the pravastatin group compared with placebo.
(B) Hypertriglyceridemia: Triglyceride levels in the range of 1.70-2.25 nunol/L can be effectively reduced by eliminating causative factors and making lifestyle changes, mainly by non-pharmacological measures such as dietary modification, weight loss, and increased physical activity. TG ≥ 5.65 mmol/L (500 me/d1), treatment is preferred to fibrates or niacin. n-3 polyunsaturated fatty acids (fish oil) 3-5 g can reduce TG by 25%-30%, and the combination of fibrates or niacin with n-3 polyunsaturated fatty acids often results in better efficacy, with few adverse drug reactions. The above treatment still can not obtain satisfactory results, the addition of statins can help to reduce TG levels.
VI. ACEI.
There are no special recommendations in the various guidelines on the application of ACEI in elderly coronary artery disease. It can be applied according to the recommendations of each guideline. There is no significant difference in the efficacy of ACEI class, the main difference is that its chemical structure contains sulfhydryl, carboxyl and phosphate groups. The route of excretion is mainly through the single channel excretion or through the renal and hepatobiliary dual channel excretion, such as Benazepril and Fosinopril. The drugs excreted via dual channel can be used in the elderly with poor renal function.
VII. Antithrombotic and anticoagulant therapy for coronary artery disease in the elderly.
A large body of evidence-based medical evidence shows that antithrombotic therapy can provide significant benefits to patients with coronary artery disease. However, in elderly patients with coronary artery disease, the trade-off between anticoagulation and the risk of bleeding is a challenge in the real world.
(i) Anticoagulation.
The ExTRACT-TIMI 25 study found that for every 1000 patients treated with enoxaparin, there were 27 fewer ischemic events and only 4 more bleeding events in patients under 75 years of age compared with usual heparin therapy, and 22 fewer ischemic events and only 2 more bleeding events in patients over 75 years of age. the ASSENT 3-PLUS study found that the application of conventional therapeutic doses of enoxaparin in people >75 years of age The Extract-TIMI25 study found that the incidence of minor and major bleeding in the enoxaparin group was 2.6% and 3.1% respectively, higher than the UFH rate of 1.8% and 1.4%, mainly in patients aged >75 years and with creatinine clearance <30 ml/min. Therefore, the 2007 STEMI guidelines recommend age-adjusted dosing of enoxaparin.
In the OASIS-5 trial, there was no difference in the effect of fondaparinux versus enoxaparin in the combined endpoints of death, myocardial infarction and intractable ischemia, but fondaparinux had a better safety profile. In elderly patients, fondaparinux reduced the absolute and relative risk of bleeding by 2.8% vs 0.7% and 50.9% vs 33.3%, respectively. in the OASIS-5 study, the incidence of bleeding was significantly higher in patients over 65 years of age than in patients under 65 years of age, but the risk of bleeding remained low compared with enoxaparinol, and no dose adjustment was required in elderly patients (>75 years) without renal impairment .
In the ACUITY study age subgroup, bivalirudin in combination with heparin and IIb/IIIa receptor antagonists was similar in the non-ST-segment elevation ACS population >75 years of age, but bleeding events were significantly reduced, with 1 major bleed avoided per 16 patients treated with bivalirudin in elderly PCI patients compared with heparin + platelet glycoprotein IIb/IIIa inhibitors, and 1 major bleed avoided per 16 patients 55 years of age Patients younger than 55 years avoided 1 major bleeding for every 38 cases treated with bivalirudin. This suggests that bivalirudin has a better safety profile in elderly patients and produces a better net clinical benefit in older patients with coronary artery disease.
The available clinical data on the use of oral factor Xa inhibitors in the morning in the elderly population are limited.
(ii) Anti-platelet therapy
The Chinese expert consensus clinical recommendations for antiplatelet therapy are.
(1) Long-term therapeutic doses of aspirin and clopidogrel need not be changed; the dose of aspirin should not exceed 100 mg/d for dual antiplatelet therapy.
(2) Use clopidogrel 75 mg/d in the acute phase, with a lower or no loading dose as appropriate.
(3) Use of platelet GP IIb/IIIa inhibitors requires rigorous assessment of bleeding risk.
(4) Use dual antiplatelet therapy in combination with proton pump inhibitors ( PPI) when combined with risk factors for gastrointestinal bleeding.
The results of the meta-analysis showed that the application of aspirin for secondary prevention was associated with a 22% reduction in the risk of the composite endpoint of cardiovascular mortality, myocardial infarction and stroke. This risk reduction was similar in the elderly and in patients aged <65 years, with 19.4% and 23.1%, respectively. The meta-analysis showed that the clinical benefit of GP IIb/IIIa receptor antagonists decreased with increasing age in patients with ACS. In patients >70 years of age, the use of GP IIb/IIIa receptor antagonists improved the efficacy by a non-statistically significant 4%, but increased the relative risk of bleeding by 62%.The TRITON-TIMI 38 study showed that the new P2Y12 receptor antagonist Pragrel, and in patients with coronary artery disease with high-risk ischemic factors, such as previous transient myocardial ischemia, stroke, age >75 years, The net benefit of prasugrel was negative in patients with risky ischemic factors such as previous transient myocardial ischemia, stroke, age >75 years, and body mass <60 kg. Therefore, prasugrel is not routinely recommended in elderly patients with coronary artery disease >75 years of age.
Studies have shown that tigretol is more effective than clopidogrel for the prevention of myocardial ischemia in both patients >65 years of age and patients ≤65 years of age. However, in the >75+ age group, the absolute reduction in myocardial ischemia with tegretol was similar to that in patients ≤75 years of age, 1.5% vs 1.8%, with a slightly reduced relative reduction of 6% vs 18%. However, in the 75+ age group, tegretol did not show a net benefit over clopidogrel.