I. Why hypertension should be treated
Cardiovascular disease is the most common cause of death and disability in modern society, and hypertension is the most important risk factor for cardiovascular disease (CVD). The global prevalence of hypertension has now reached 31.3%, and deaths from this disease account for 6% of deaths worldwide each year. Whether blood pressure is up to standard is an important weight in determining cardiovascular health and the quality of life in the second half of life.
The guidelines for the prevention and treatment of hypertension state that “the relationship between blood pressure and risk of cardiovascular events is continuous, consistent, and independent of other risk factors. The higher the blood pressure, the higher the risk of myocardial infarction, heart failure, stroke and kidney disease.
Antihypertensive treatment reduces stroke events by 35 to 45 percent; myocardial infarction by 20 to 25 percent; and heart failure by more than 50 percent.” Because lowering blood pressure below 140/90 mmHg reduces CVD complications, the JNC 7 guidelines specify a blood pressure control goal of <140/90 mmHg for patients with essential hypertension in general and <130/80 mmHg for patients with combined diabetes or kidney disease.
Medical authorities around the world have recognized that strict blood pressure control is a powerful tool for improving the prognosis of cardiovascular disease, and hypertension treatment strategies have indeed undergone a dramatic improvement over the past 30 years, but the rate of blood pressure control has not improved as much as desired relative to the continuing increase in prevalence.
In our country, due to more limited medical resources and less popular health education than in developed countries, the awareness rate of hypertension is only 30.2%, the treatment rate is 24.7%, and the control rate is 6.1%; although it has improved compared with 26.6%, 12.2%, and 2.9% in 1991, it is still at a poor level.
Second, why hypertension should be drug combination therapy
The most important reason why hypertension is difficult to control is the multiplicity of pathogenesis. Its pathogenesis involves multiple aspects such as the renin-angiotensin-aldosterone system, the sympathetic nervous system, and the humoral volume system. A drug can often only be adjusted for one of these mechanisms, and thus the efficacy is poor. The lowering of blood pressure will inevitably activate the body’s feedback mechanism, causing blood pressure to rise again, and after the drug is increased to the dose-response plateau, increasing the dose will not only not increase the efficacy, but also lead to a significant increase in adverse effects. Therefore, more than 50% of hypertensive patients cannot achieve the blood pressure standard with one drug, and the response rate of monotherapy is only 40%-60%.
1. Combination therapy – shortcut to achieve the standard
(a) the advantages of combination therapy Combination therapy has the following advantages: (1) a variety of drugs combined through different mechanisms to lower blood pressure, complement each other; (2) the complementary effect of different classes of drugs can prevent the offset mechanism after the addition of a single drug; (3) the combination of drugs with different peak effect times may prolong the duration of antihypertensive effect; (4) the combination of drugs generally requires only a small dose, reducing the occurrence of adverse reactions; (5) Enhance the protective effect on target organs, and the combination of drugs can increase the response rate to 75%-90%.
(ii) Evidence-based medical evidence supporting combination therapy Many large clinical studies, such as ALLHAT, HOT, VALUE, LIFE, and ASCOT, have fully demonstrated the need for combination therapy in patients with moderate to severe hypertension.
In the ALLHAT study, the starting dose of amlodipine 2.5 mg/d, lenopril 10 mg/d or chlorthalidone 12.5 mg/d was used to achieve a standard rate of less than 40% for single antihypertensive drugs and more than 60% for combination of two drugs at 5 years of follow-up.
The aim of the HOT study was to find the most appropriate level of blood pressure reduction with a regimen of felodipine 5 mg/d. Other drugs such as angiotensin-converting enzyme inhibitors and beta-blockers were added if necessary. At the beginning of the study the mean blood pressure of the patients was 161/98 mmHg and only about 40% of the patients were on combination therapy, whereas by the end of the trial the mean blood pressure of the patients was 142/83 mmHg and 68% were on combination therapy. In addition, 700 patients were randomized to the three target DBP groups of 90 mmHg, 85 mmHg, and 80 mmHg, and the use of combination therapy increased as the target blood pressure decreased: 37% of patients in the 90 mmHg group were treated with monotherapy, 32% in the 85 mmHg group, and 25% in the 80 mmHg group, meaning that for every 5 mmHg decrease in target blood pressure, the proportion of patients requiring combination therapy This means that for every 5 mmHg reduction in target blood pressure, there is a corresponding 5% increase in the number of patients requiring combination therapy.
Patients enrolled in the VALUE study were “treated or untreated hypertensive patients with untreated hypertension, SBP 160-210 mm Hg and DBP 95-105 mm Hg, and those aged ≥50 years at high risk for cardiovascular events”, treated with ARB valsartan or amlodipine based antihypertensive therapy, respectively. The results also showed that only 1/3 of these high-risk hypertensive patients were treated effectively with monotherapy.
The LIFE study was a trial comparing the antihypertensive and prognostic effects of ARB valsartan with atenolol (plus HCTZ and other drugs if necessary) in 9193 hypertensive patients aged 55 to 80 years with combined left ventricular hypertrophy, with 68% and 63% of patients in the two groups receiving the combination at the end of follow-up, respectively.
The ASCOT study compared the efficacy of two commonly used antihypertensive combinations (ACE inhibitor + CCB vs. beta-blocker + diuretic) in patients with hypertension, with an average of 2.2 and 2.3 antihypertensive drugs used in the two groups after 5.5 years of follow-up, and ultimately 85% and 91% of those requiring a combination in the amlodipine and atenolol groups, respectively. The above studies show that most hypertensive patients need to use multiple drugs in combination to achieve the blood pressure standard (Fig. 1 The average number of antihypertensive drugs used in several large antihypertensive studies), and the most clinically used and currently more popular combination regimens are ARB/ACEI + diuretics and ACEI/ARB + CCB.
(C) Europe and the United States hypertension guidelines on the combination of treatment recommendations because the combination of treatment has the advantages of monotherapy is difficult to compare, and can significantly improve the rate of blood pressure control.
The US JNC 7 antihypertensive treatment protocol states: “To achieve the blood pressure target, most hypertensive patients need a combination of two or more antihypertensive drugs. If blood pressure exceeds the target blood pressure by more than 20/10 mmHg, a combination of 2 or more antihypertensive drugs should be considered, either prescribed separately or in combination.”
The European Guidelines for the Treatment of Hypertension, published in 2003, also state that “the emphasis on the preference for a particular drug to lower blood pressure is outdated, as most patients require the application of 2 or more drugs to bring blood pressure to target levels.”
The latest Chinese guidelines for hypertension, which are based on the latest research findings and guideline recommendations from home and abroad, also provide a detailed description of combination therapy. The guidelines state that “in order to maximize the effectiveness of hypertension treatment, a greater reduction in blood pressure is required, which is often beyond the reach of monotherapy and is prone to adverse effects with increased doses of single drugs. Randomized clinical trials have demonstrated that most hypertensive patients require two or more antihypertensive drugs to control their blood pressure, and that there is a need and value in combining drugs. The dose of each drug is not large when combined, and the therapeutic effects of the drugs should be synergistic or at least additive, and their adverse effects can cancel each other out or at least not overlap or add up. The number of drugs used in combination should not be excessive to avoid complex drug interactions. A reasonable formulation should also take into account the consistency of the duration of action of each drug and the optimization of the dose ratio of the dispensed components. Therefore, the combination of drugs should have its rational pharmacological basis”.
For the first time, the relative advantages of various antihypertensive drugs are made explicit in the Latest Chinese Guidelines on Hypertension: “Prevention of stroke: ARBs are superior to β-blockers and calcium antagonists are superior to diuretics; prevention of heart failure: diuretics are superior to other classes; delay of renal insufficiency in diabetic and non-diabetic nephropathy: ACE inhibitors or ARBs are superior to other classes; improvement of left ventricular hypertrophy. ARB over β-blockers; delaying carotid atherosclerosis: calcium antagonists over diuretics or β-blockers”.
Under the principle of combination therapy, the combination of ACE inhibitor or ARB + CCB or diuretic can take into account the protective effect on all organs of the body.
Evidence has accumulated on the unique target organ protection and improved glucose metabolism beyond antihypertensive effects of RAS systemic blockers. In view of the good antihypertensive and target organ protective effects of RAS system blockers, which are in line with the current trend of hypertension treatment, the US JNC 7 guidelines, the European Guidelines for Hypertension and the Chinese Guidelines for the Prevention and Treatment of Hypertension (2005 Revision) all affirm the use of RAS system blockers – ACEI and ARB – in the treatment of hypertension on the basis of a large amount of evidence-based medical evidence. ACEI and ARB are important in the treatment of hypertension, especially for patients with heart failure, myocardial infarction, coronary artery disease, diabetes mellitus, chronic kidney disease and other complications and those with high-risk factors, RAS system blockers have become indispensable first-line therapeutic agents.
In clinical work, it is common to combine RAS system blockers with drugs such as CCB or diuretics, so that both the volume of elevated blood pressure and the pathogenesis of RAS are effectively curbed simultaneously. The benefits of combining a RAS system blocker with a CCB include: the natriuretic effect of the CCB is complementary to that of the ACE inhibitor; the CCB and the RAS system blocker dilate blood vessels by different mechanisms; the ACE inhibitor primarily dilates small renal outflow arteries while the CCB primarily dilates small inlet arteries; and the ACE inhibitor reduces peripheral edema caused by dihydropyridine CCBs.
The benefits of combining RAS system blockers with diuretics are: the combination of RAS system blockers and thiazide diuretics can block both the RAS mechanism and the volume mechanism of hypertension, and the two have synergistic effects in lowering blood pressure: diuretics reduce plasma volume and cause negative sodium balance in the body, especially in vascular smooth muscle cells, resulting in a decrease in peripheral resistance and thus lowering blood pressure, but the decrease in plasma volume The RAS system blocker can inhibit the RAS system, thus producing a synergistic effect with diuretics in lowering blood pressure; at the same time, the RAS system blocker can also counteract the adverse effects of diuretics caused by increased aldosterone, such as hypokalemia. Therefore, the combined use of the two enhances the antihypertensive effect and reduces the adverse effects.
The combination of ARB + diuretics has become a classic combination of combination drugs due to a series of unique advantages such as comprehensive protection of target organs, improvement of glucose metabolism and rare adverse reactions.
Blood pressure levels maintain self-balance through many complex biochemical, physiological and anatomical interactions, and a single factor rarely raises blood pressure. Most hypertension is multifactorial in etiology, including the role of genetic and environmental factors that regulate blood pressure levels through many intermediate systems. Anti-hypertensive drugs act through these intermediate systems and act on specific targets to achieve blood pressure lowering effects.
3. 3 basic principles in the treatment of hypertension:
1. In order to effectively prevent target organ damage, a basic classification of blood pressure fluctuation types is required, preferably under 24-hour ambulatory blood pressure monitoring, to make the most preliminary choice for different types.
2. For patients with spoon type hypertension, it is best to give the corresponding drug with a shorter duration of action before the peak of hypertension, requiring blood pressure to be stable within the target range for 24 hours a day; for patients with non-spoon type hypertension, it is best to use a controlled-release or extended-release drug that lasts for 24 hours once a day.
3. Use a smaller effective dose to obtain the possible efficacy with minimal adverse effects, if the effect is not satisfactory, the dose can be gradually increased to obtain the best efficacy. In order to increase the antihypertensive effect without increasing adverse reactions, two or more antihypertensive drugs can be used in combination.