Guidelines for Combination Therapy for Hypertension: Principles, Regimens, and Treatment of Comorbidities

Which type of antihypertensive drug should be chosen when hypertension is complicated by heart failure? Heart failure is a major complication of hypertension and one of the consequences of its progression. Long-term hypertension affects the heart, causing damage in two ways: myocardial hypertrophy and coronary atherosclerosis. In the early stages, myocardial hypertrophy and decreased ventricular diastolic function occur; in later stages, decreased cardiac systolic function and cardiac enlargement lead to heart failure. The main goal of treating hypertension and heart failure is to control arterial blood pressure, reduce excessive pressure load on the right ventricle, reduce excessive volume load in heart failure, increase cardiac output, reduce organ congestion, and improve coronary artery blood supply and cardiac systolic and diastolic function. When using medication, it is best to choose antihypertensive drugs with dual effects, effectively lowering blood pressure and treating heart failure. The most suitable drugs are as follows.

① Angiotensin-converting enzyme inhibitors (ACEIs): These drugs significantly improve left ventricular systolic function and reduce cardiac ejection capacity, thereby improving heart failure symptoms. They are currently the first-line drugs effectively reducing disability and mortality rates in heart failure patients and are clinically considered the first-line treatment for hypertension complicated by heart failure. For patients with hypertension and chronic heart failure, long-acting formulations (such as perindopril and enalapril) are preferred. In addition, angiotensin II receptor blockers (ARBs) can also be used to treat complications.

② Diuretics: Diuretics have a mild antihypertensive effect and can also be used as adjunctive therapy for heart failure. Hydrochlorothiazide, for example, reduces blood volume, thereby reducing cardiac load and improving cardiac function; it is a commonly used drug for treating this condition.

③ Beta-blockers: Such as metoprolol, should be started at the lowest possible dose. They can safely and effectively treat hypertension complicated by heart failure, reducing the risk of cardiac death and hospitalization rates in heart failure patients. ④ Calcium channel blockers: This drug is suitable for patients with early-stage heart failure. Because it has a mild effect of weakening cardiac contractility, it should be used with caution in patients with severe heart failure. Non-dihydropyridine calcium channel blockers are contraindicated.

⑤ Alpha-receptor blockers: This drug is suitable for hypertension complicated by heart failure. The dosage starts at 0.5–1.0 mg every 6–8 hours, and can be gradually increased to 2–3 mg per dose. Blood pressure should be monitored closely during treatment.

How should antihypertensive drugs be selected for hypertension complicated by renal insufficiency? The most important way to delay renal insufficiency is to lower the blood pressure that damages the kidneys to below 130/80 mmHg. It has been proven that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) are beneficial in controlling the progression of diabetic nephropathy and non-diabetic nephropathy. ACEIs or ARBs can only increase serum creatinine levels by 35% compared to pre-treatment levels; therefore, they should not be discontinued unless hyperkalemia occurs. In patients with severe kidney disease, thiazide diuretics are not very effective, requiring increased doses of diuretics (furosemide) and combination therapy with other medications. Potassium-sparing diuretics (such as spironolactone) are contraindicated in patients with renal insufficiency. In patients with elevated serum creatinine levels, when using ACEIs, the initial dose should be small, and the increase should be slow, closely monitoring changes in serum creatinine and potassium levels. Combination Therapy for Antihypertensive Drugs

When should combination therapy be considered?

① When a single drug is effective but not ideal;

② When other diseases coexist and the dosage of certain drugs is limited;

③ Hypertensive patients with significant target organ damage;

④ Patients with refractory hypertension.

Why is combination therapy considered the foundation of hypertension treatment? Hypertension treatment often requires the combined use of two or more drugs to achieve target blood pressure. The main reasons are as follows:

① Monotherapy is not ideal: Monotherapy rarely achieves target blood pressure, with a success rate of only 20%–50%, and increasing the dose easily leads to adverse reactions. Combination therapy can increase the target blood pressure achievement rate to 75%–90%. This is because monotherapy, after lowering blood pressure, activates compensatory mechanisms that regulate blood pressure, restoring it to pre-medication levels. For example, diuretics lower blood pressure by dilating blood vessels and promoting sodium excretion, but the resulting decrease in sodium levels and vasodilation can reflexively activate mechanisms that regulate blood pressure. Combining this with beta-blockers can block sympathetic nerve excitation, inhibit renin release, enhance the antihypertensive effect of diuretics, and counteract their adverse reactions.

② Combination therapy can protect vital organs: Different classes of antihypertensive drugs offer varying degrees of protection to vital organs such as the heart, brain, and kidneys. Calcium channel blockers (CCBs) are most effective in stroke prevention; ACEIs and ARBs can reverse left ventricular hypertrophy, reduce proteinuria, and delay renal insufficiency caused by diabetic nephropathy or non-diabetic nephropathy; beta-blockers and ACEIs can improve the prognosis of patients with concurrent heart failure. Therefore, combination therapy can protect target organs through different mechanisms. ③ Combination therapy can reduce the dosage of a single drug and counteract adverse reactions caused by different drugs: For example, diuretics can cause hypokalemia, which can be avoided by combining them with ACEIs or potassium-sparing diuretics; CCBs can cause edema and increased heart rate, which can be alleviated by combining them with ACEIs; and β-blockers can prevent increased heart rate.

What are the principles of combined use of antihypertensive drugs? The use of antihypertensive drugs must follow certain principles to achieve the best effect through combination therapy. The principles are as follows:

① It is not recommended to combine antihypertensive drugs of the same class, such as nifedipine with nifedipine or metoprolol with labetalol, as this does more harm than good. However, there are exceptions, such as the dihydropyridine calcium channel blocker nifedipine and the non-dihydropyridine calcium channel blocker verapamil extended-release tablets, which can be used in combination to counteract adverse reactions.

② The combined use of antihypertensive drugs should follow the principle of improving the antihypertensive effect, preventing compensatory reactions triggered by blood pressure reduction during monotherapy, improving antihypertensive efficacy, and increasing patient tolerance.

③ Combined use should follow the principle of reducing adverse reactions.

④ Adhere to the principle of low dosage; the combined use of two or more low-dose drugs can complement each other's advantages. What are the opinions of the 2005 Chinese Guidelines for the Prevention and Treatment of Hypertension? The 2005 Chinese Guidelines for the Prevention and Treatment of Hypertension state that for patients with stage 2 hypertension and high-risk patients, a two-drug combination therapy can be considered from the outset, with the drug combination regimen being the same as the 2003 European Hypertension Guidelines. Commonly used combinations are as follows:

① ARB or ACEI and diuretics;

② ARB or ACEI and CCB;

③ β-blockers and diuretics;

④ CCBs and diuretics;

⑤ Dihydropyridine CCBs and β-blockers;

⑥ α-blockers and β-blockers.

How should antihypertensive drugs be selected in combination for special populations? For special populations such as those with coronary heart disease, cerebrovascular disease, abnormal glucose and lipid metabolism, or those assessed as having a high risk of myocardial infarction and stroke (>20% over 10 years), if there are no contraindications, ARBs (such as telmisartan) or ACEIs should be the first choice. If blood pressure is not controlled after 4-5 weeks of medication, a second drug should be added. When adding a second drug, the following combination therapy regimens should be considered:

① Because ARBs and ACEIs have potassium-sparing effects, combining them with thiazide dimethoate drugs has unique advantages, and the efficacy is greater than that of a single drug. Therefore, this combination should be the first choice: hydrochlorothiazide (<25mg/day) or indapamide (<2.5mg/day), with a low dose. If blood pressure is not controlled after 4-5 weeks of medication, a third drug should be considered.

② If the patient has a fast heart rate, a beta-blocker (bisoprolol, metoprolol) should be added, while dihydropyridine calcium channel blockers should be avoided.

③ If the patient has congestive heart failure, a beta-blocker (metoprolol, bisoprolol) should be used in combination, while calcium channel blockers should be avoided.

④ If the patient has coronary atherosclerotic angina, a beta-blocker (metoprolol, bisoprolol) should be used in combination.

⑤ If the patient has a slow heart rate, dihydropyridine drugs (such as amlodipine, nifedipine sustained-release tablets) should be used in combination, while beta-blockers should be avoided.

⑥ If the patient frequently experiences angina attacks at night, nifedipine sustained-release tablets should be used in combination.

How to correctly understand and use compound preparations? Compound preparations refer to preparations containing two or more drug components in the same tablet (or other dosage form) (including compound preparations combining traditional Chinese and Western medicine). Compound antihypertensive tablets and Compound Antihypertensive Tablets (Antihypertensive No. 0) are commonly used compound preparations in clinical practice in my country. The main components of Compound Antihypertensive Tablets are reserpine 0.03125mg, hydralazine 3.125mg, hydrochlorothiazide 3.125mg, chlorpyrifos 2mg, and potassium chloride 30mg. Compound Antihypertensive No. 0 has the same main components, but at three times the dosage. It is a long-acting formulation taken once daily, with definite efficacy, few adverse reactions, and a lower price. These two compound preparations have played a significant role in the history of hypertension treatment in my country. However, because both contain reserpine, they have potential adverse reactions, such as causing depression, excessive gastric acid secretion, sexual dysfunction, and carcinogenicity. Therefore, the scientific validity of these two drug formulations and their suitability for modern hypertension treatment are subject to considerable debate in the academic community. In recent years, numerous large-scale clinical trials have demonstrated satisfactory antihypertensive effects from combining low-dose reserpine with diuretics, or from compound preparations containing reserpine and diuretics. Given its low cost, reserpine remains a primary antihypertensive drug and component of compound preparations in many countries. Many large-scale clinical trials have also proven that the combined use of reserpine and hydrochlorothiazide can significantly lower blood pressure and reduce the incidence of cardiovascular events. Therefore, scholars believe that the combined use of reserpine and hydrochlorothiazide is scientifically sound and inexpensive, making it suitable for a wide range of low-income patients with mild to moderate hypertension. However, when choosing to use these two compound preparations, the indications must be carefully considered. Compound preparations containing high-dose thiazide diuretics should be used with caution in patients with hypertension accompanied by diabetes or dyslipidemia. Middle-aged and elderly individuals taking preparations primarily containing reserpine should pay attention to mental symptoms; if depressive symptoms occur, the medication should be discontinued immediately to avoid accidents. Patients with gastritis or gastric ulcers should not take compound antihypertensive tablets to avoid aggravating ulcers and causing gastrointestinal bleeding. With the development of pharmaceutical science, new compound preparations suitable for different populations are constantly being introduced. For example, each tablet of compound captopril (Kaifute) contains 10mg captopril and 6mg hydrochlorothiazide, while Hyzait contains losartan and hydrochlorothiazide. Both have significant therapeutic effects and can be selected under the guidance of a doctor.