Zofenopril and diuretics: a combination of new possibilities

Scientific research has proven that increased arterial blood pressure is directly related to the relative risk of stroke and heart disease. Almost a quarter of a century ago (in 1990), a meta-analysis of nine prospective observational studies (420 thousand patients) showed that by reducing the usual diastolic blood pressure by 5 mm Hg, 7.5 mm Hg, and 10 mm Hg, the risk of stroke decreased by 34, 46, and 56 percent respectively, and the risk of ischemic heart disease by 21, 29, and 37 percent respectively. According to data from other meta-analyses (17 randomized trials, 37 thousand patients with hypertension), a 5-year treatment with beta-blockers or diuretics significantly reduced the risk of major cardiovascular events (CVD) as follows: • Stroke - 42%; • Ischemic heart disease - 14%; • Mortality from CVD - 21%. Subsequent studies indicate that treating hypertension with RAAS-acting drugs - angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), and calcium channel blockers (CCBs) can significantly reduce the frequency of CVD complications. These drugs have shown reliable cardioprotective effects in patients of various ages including those at a high risk of cardiovascular disease. Clinical trials show that achieving and maintaining target blood pressure is usually successful (in 60-70% of cases) by treating with combinations of two or more antihypertensive drugs, while monotherapy is effective in only 30% of cases. Combination therapy with antihypertensive drugs is almost always necessary for patients at high risk of CVD: older individuals; those with heart and vascular diseases; those with metabolic syndrome, dyslipidemia, and other concurrent clinical conditions. The Hypertension Optimal Treatment (HOT) study revealed that antihypertensive treatment resulted in normal diastolic blood pressure (<= 90 mm Hg) in 85% of patients, but monotherapy only benefited one-third of patients. The same study suggested that a combination of two low-dose drugs effectively controlled hypertension in 30% of patients. According to the UK Prospective Diabetes Study (UKPDS), treating arterial hypertension and type 2 diabetes over an 8.4-year period significantly cut down on fatal and non-fatal microvascular and macrovascular complications. In this study, two-thirds of patients received a combination of antihypertensive drugs for their treatment regime. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) included 33,357 arterial hypertension patients with at least one other CVD risk factor who received treatment with the thiazide diuretic chlorthalidone, amlodipine, or lisinopril. At the conclusion of the study, after 4.9 years, around 40% of patients were using a combination therapy of antihypertensive drugs to maintain target blood pressure. The Controlled ONset Verapamil Investigation of Cardiovascular End Points (CONVINCE) study provided data from 16,602 patients with arterial hypertension and at least one CVD risk factor. All patients received random treatment with verapamil, atenolol, or hydrochlorothiazide. According to study data, 80% of participants were using a combination of drugs to maintain target blood pressure three years after the initiation of the study. Almost all participants in the VALUE (Valsartan Antihypertensive Long-term Use Evaluation) study, high-risk CVD patients, were using a combination of two or more antihypertensive drugs at the end of the study to maintain stable normotension. In one of the latest studies, HYVET (HYpertension in the Very Elderly), which followed patients aged 80 years or older with isolated systolic hypertension, after 1.8 years from the start of the study, 73% of patients were receiving combination antihypertensive therapy.

Combinations - optional treatment

Nowadays, an important tactic for controlling hypertension has become the treatment with combinations of antihypertensive drugs because it is: • effective; • preferable as an alternative to increasing monotherapy doses; • safer, better tolerated, and less likely to cause side effects than prescribing a single drug at maximum doses. The latest hypertension treatment guidelines suggest the use of combinations of antihypertensive drugs for the majority of patients with arterial hypertension, especially when initial monotherapy proves ineffective. These guidelines advise an immediate start of combination therapy when: Doctors diagnose 2nd-degree (or moderate) hypertension: systolic blood pressure 160–179 mm Hg and/or diastolic blood pressure 100–109 mm Hg; • The diagnosis is 1st-degree (or mild) hypertension (systolic blood pressure 140–159 mm Hg and/or diastolic blood pressure 90–99 mm Hg), but the patient also has concomitant diseases, or organ damage: diabetes, ischemic heart disease, etc.

Combinations of ACE Inhibitors and Diuretics: Clinical Significance

In clinical practice, combinations of various pharmacological groups of drugs are now used to treat arterial hypertension, whose effectiveness and safety have been proven by reliable scientific studies. The most commonly recommended combinations are: • beta-blockers and diuretics; • calcium channel blockers and beta-blockers; • calcium channel blockers and angiotensin II receptor blockers; • calcium channel blockers and angiotensin-converting enzyme inhibitors. Recent studies have shown that in some important clinical aspects, combinations of ACE inhibitor and diuretic may outperform other popular combinations. The combination of an ACE inhibitor and a diuretic:

• The combination effectively reduces elevated blood pressure, with a positive therapeutic response rate of > 80% in cases of mild or moderate hypertension.
• The components in the combination work together but affect different pathways in the renin-aldosterone-angiotensin system (RAAS).
• Administration of a diuretic decreases plasma sodium, stimulating the RAAS and enhancing the effect of the ACE inhibitor.
• The ACE inhibitor in the combination inhibits the formation of angiotensin II, which in turn, increases the antihypertensive effect of the diuretic.
• ACE inhibitors can decrease reactive hyperreninemia triggered by the diuretic, thus leading to a reduction in blood pressure.
• Using both an ACE inhibitor and a diuretic allows us to achieve the maximum antihypertensive effect tied to the reduction of plasma sodium levels.
• The effectiveness of the combination does not diminish with long-term use.
• Thanks to pharmacological synergy, we require lower doses of the components to achieve the same hypotensive effect compared to prescribing these drugs individually, which contributes to better treatment tolerance.
• The risk of unwanted metabolic side effects is significantly lower with small doses of hydrochlorothiazide (12.5 or 25 mg/day) compared to a 50 mg/day dose.
• By suppressing the activity of the RAAS system, ACE inhibitors reduce the loss of potassium and bicarbonates induced by diuretics, thereby countering the unwanted diuretic effect on electrolyte balance.

Recent clinical studies have shown that combinations of ACE inhibitors and diuretics not only effectively reduce elevated blood pressure but also have a protective effect on target organs, primarily the heart and kidneys. It has been proven that treatment with a combination of an ACE inhibitor and a diuretic significantly slows down the progression of diabetic and other etiologies of nephropathy.

Zofenopril and Hydrochlorothiazide: Specifics and Opportunities

In clinical practice, the zofenopril calcium salt is a prodrug - in the body, it is converted into the pharmacologically active substance zofenoprilat (salt). Zofenopril calcium salt (zofenopril, Zofistar) is a highly lipophilic ACE inhibitor with a long-lasting Penetration into tissues and stable inhibition of myocardial ACE. This provides zofenopril with clinically significant antioxidant and cardioprotective properties, such as the ability to improve endothelial function and effectively use it to treat not only hypertension but also myocardial infarction. Clinical studies have shown that zofenopril is well tolerated and beneficial for patients with acute myocardial infarction, heart failure, primary arterial hypertension. In six double-blind placebo-controlled variable dose studies involving approximately 1600 patients with mild or moderate primary hypertension, treatment with 30-60 mg/day zofenopril for 6-8 weeks significantly reduced elevated blood pressure compared to placebo. In twelve randomized double-blind actively controlled comparative trials involving approximately 3200 patients with mild or moderate hypertension (diastolic blood pressure 90-114 mm Hg), zofenopril also effectively reduced elevated blood pressure like atenolol, amlodipine, hydrochlorothiazide, enalapril, lisinopril, losartan, or candesartan [Figure 1]. The lipophilic properties of zofenopril pharmacologically complement hydrochlorothiazide, as this drug affects the plasma and tissue concentration of ACE inhibitors, which depends on the specific ACE inhibitor used. For example, experimental studies with rat myocardial infarction models showed that hydrochlorothiazide increased the concentration of lipophilic zofenopril in heart and kidney tissues, but not in plasma. Co-administered with hydrophilic lisinopril, hydrochlorothiazide increased the concentration of lisinopril in plasma but not in target organs' tissues. It has been experimentally determined that the combination of zofenopril and hydrochlorothiazide has a specific kidney-sparing effect, which is reliably manifested in the presence of kidney damage (nephropathy). There is increasing clinical data on the antioxidant and cardioprotective effects of zofenopril. Fixed-dose combinations of zofenopril and hydrochlorothiazide 30/12.5 mg, intended for once-daily use, are registered in several European Union countries for the treatment of mild or moderate hypertension if monotherapy with zofenopril or hydrochlorothiazide is insufficiently effective. Larger studies are currently underway to assess the effectiveness of higher doses of zofenopril (60 mg/day) combined with 12.5 mg/day hydrochlorothiazide in patients with arterial hypertension and having at least three additional cardiovascular risk factors from these: hyperglycemia, hyperlipidemia, obesity, family history of early cardiovascular disease, smokers. Studies have shown that the combination of zofenopril and hydrochlorothiazide 30/12.5 mg/day (Z/HCT 30/12.5 mg) is significantly more effective than treatment with these drugs individually. In a study involving 600 patients with mild or moderate hypertension, the Z/HCT 30/12.5 mg combination: • Acted more actively as an antihypertensive than zofenopril or hydrochlorothiazide monotherapy; • Was effective even for those patients for whom zofenopril 30 mg monotherapy was not effective; • Was more effective than monotherapy with zofenopril and hydrochlorothiazide for high cardiovascular risk patients (those with metabolic syndrome, diabetes, atherogenic dyslipidemia, chronic kidney disease, or other cardiovascular risk factors).

Search for optimal doses

Clinical studies confirm that combinations of antihypertensive drugs containing 12.5 mg of hydrochlorothiazide are significantly more effective than single antihypertensive drug treatment. Study data show that administering Z/HCT 30/12.5 mg or zofenopril and hydrochlorothiazide 60/12.5 mg once a day for 12 weeks led to normal diastolic blood pressure in 57 and 79 percent of patients, respectively.

Among patients whose diastolic blood pressure normalized or decreased by > 10 mm Hg compared to the initial measure, but remained at 90 mm Hg or higher while being treated with the combination of zofenopril and hydrochlorothiazide, 80 and 93 percent respectively experienced these results.

Researchers have conducted several studies to determine the optimal doses of the zofenopril and hydrochlorothiazide combination. In these studies, patients with mild or moderate hypertension received various combinations of zofenopril 15, 30, or 60 mg and hydrochlorothiazide 12.5 or 25 mg once a day. The studies demonstrated that the best blood pressure control per day occurred when taking 30 or 60 mg of zofenopril and 12.5 mg of hydrochlorothiazide once a day.

The findings also indicate that the combination of zofenopril and hydrochlorothiazide provides moderate and consistent blood pressure control throughout the day. After evaluating various studies, researchers determined that the Z/HCT 30/12.5 mg combination offers optimal effectiveness and safety. Therefore, this dosage of the combination was used in subsequent comparative studies.

Comparative studies

The efficacy and safety of the Z/HCT 30/12.5 mg combination were evaluated in two multicenter phase III double-blind studies, comparing it with each component's monotherapy. In one of these studies, 463 patients with mild or moderate hypertension (diastolic blood pressure 95–110 mm Hg) were treated with the Z/HCT 30/12.5 mg combination or each component alone for 12 weeks. After 12 weeks, patients who normalized or had a positive therapeutic response to blood pressure were significantly more in the group taking Z/HCT 30/12.5 mg compared to patients taking only zofenopril. In the second study, 369 patients with mild or moderate hypertension who had an ineffective 4-week double-blind treatment with 30 mg/day of zofenopril (blood pressure remained at 130/80 mm Hg or higher; or the response to treatment was inadequate: systolic blood pressure decreased by < 20, and diastolic by < 10 mm Hg). These patients were treated with the Z/HCT 30/12.5 mg combination or zofenopril alone for 8 weeks. It was found that the Z/HCT 30/12.5 mg combination significantly reduced blood pressure more than zofenopril monotherapy, and the group taking Z/HCT 30/12.5 mg achieved a therapeutic response significantly more frequently than the zofenopril monotherapy group. Continuing the treatment for another 6 weeks, blood pressure continued to decrease in patients taking Z/HCT 30/12.5 mg, while there was no change in the zofenopril group.

Antihypertensive treatment and metabolic syndrome

For a patient with arterial hypertension and metabolic syndrome, treatment should be selected that not only does not worsen but even improves lipid and glycemic metabolism. Metabolic syndrome.Increases the risk of fatal and non-fatal cardiovascular disease complications 2-3 times compared to healthy individuals. In the presence of diabetes mellitus, the risk of cardiovascular disease increases by 5 times. Studies show that one of the best options for these patients would be an ACE inhibitor. One of the latest meta-analyses (12 randomized controlled trials) showed that treating these patients with an ACE inhibitor resulted in a 27% reduction in new cases of diabetes. The benefit of ACE inhibitors has been proven in hypertension, complicated by obesity or dyslipidemia. Taking into account the proven benefits of the ACE inhibitor zofenopril in diabetes and myocardial infarction in previous studies, the effect of zofenopril on other patient subgroups was evaluated in post-hoc analysis: patients with diabetes, metabolic syndrome, atherogenic dyslipidemia without obvious signs of heart and vascular disease. The analysis showed that:

• The fixed-dose combination of Z/HCT 30/12.5 mg reduced elevated blood pressure equally effectively among patients with and without metabolic syndrome.
• The fixed-dose combination of Z/HCT 30/12.5 mg decreased high blood pressure more effectively than treatment with zofenopril 30 mg alone, irrespective of the patient's metabolic profile.
• The antihypertensive benefit of the Z/HCT 30/12.5 mg fixed-dose combination, compared to monotherapy with zofenopril 30 mg, was more pronounced in individuals with metabolic syndrome. In the presence of metabolic syndrome, the Z/HCT 30/12.5 mg combination reduced systolic blood pressure by 9.8 mm Hg and diastolic blood pressure by 4.4 mm Hg more than monotherapy with zofenopril 30 mg. In patients with hypertension without metabolic syndrome, the reductions were 3.5 and 8.5 mm Hg, respectively.

The advantage of the Z/HCT 30/12.5 mg combination over monotherapy was also observed in individuals at highest cardiovascular risk. This was also reflected in a more pronounced decrease in systolic blood pressure. Patients with metabolic syndrome are more likely than others to suffer from treatment-resistant hypertension, often requiring more than one antihypertensive drug for adequate blood pressure control. The benefit of the Z/HCT 30/12.5 mg combination was demonstrated in patients with increased glycemia on an empty stomach. This group includes individuals with impaired glucose tolerance or diabetes - both of these conditions are often associated with metabolic syndrome. The analysis showed that a 12-week treatment with the Z/HCT 30/12.5 mg combination more effectively reduced the blood pressure of these patients, especially systolic blood pressure, than monotherapy with zofenopril 30 mg. Elevated low-density lipoprotein cholesterol concentration is an important factor promoting the development and progression of atherosclerosis. Along with the increase in this lipid fraction, an elevated triglyceride level and decreased high-density lipoprotein cholesterol concentration are often found. These three lipid fractions are metabolically related and can act atherogenically, but in different ways. Moderately elevated triglyceride levels, increased low-density lipoprotein cholesterol (LDL-C) concentration, and low high-density lipoprotein cholesterol (HDL-C) concentration share a common term - atherogenic lipoprotein phenotype. Atherogenic dyslipidemia is called the lipid triad: • Low HDL-C concentration (<40 mg/dl for men and <50 mg/dl for women); • Increased LDL-C concentration (100 mg/dl or more); • Increased triglyceride concentration(150 mg/dl or higher). According to post hoc analysis data, in the presence of atherogenic dyslipidemia, the combination of Z/HCT 30/12.5 mg more effectively reduced elevated blood pressure than zofenopril 30 mg, and the difference in systolic blood pressure reduction between the two patient groups was statistically significant. Therefore, in the presence of metabolic syndrome or high CVD risk, when hypertension control is often more challenging, the Z/HCT 30/12.5 mg combination more effectively reduced elevated blood pressure than monotherapy with zofenopril 30 mg. On the other hand, patients tolerated treatment with Z/HCT 30/12.5 mg and zofenopril 30 mg similarly well, and the tolerability of these drugs was not dependent on the metabolic patient profile.

Kidney Dysfunction

Patients with arterial hypertension often have impaired kidney function. Scientific studies show that kidney dysfunction in hypertension reliably reflects the likelihood of developing CVD complications in the future. The latest meta-analyses show that ACE inhibitors or ARBs can reliably slow the progression of kidney dysfunction due to their kidney-sparing effects. Based on the results of these studies, the European HTN diagnostic and treatment guidelines indicate that patients with arterial hypertension should routinely undergo creatinine clearance evaluation to assess the risk of organ damage. The guidelines also state that ACE inhibitors and ARBs (sartans), as monotherapy or in combination with other drugs, are optional medications for treating hypertension and kidney disease. Post hoc analysis showed that: •    The Z/HCT 30/12.5 mg combination effectively reduced elevated blood pressure similarly regardless of the degree of kidney impairment; •    The Z/HCT 30/12.5 mg combination had a more hypotensive effect on these patients than zofenopril 30 mg monotherapy, especially in cases of mild to moderate kidney impairment (creatinine clearance of 60–89 and 30–59 ml/min, respectively). In summary, treatment with zofenopril or the combination of zofenopril and a thiazide diuretic effectively reduces elevated blood pressure in hypertension and kidney dysfunction.

Treatment in the presence of cardiovascular disease risk

Patients at high CVD risk are more likely to suffer from treatment-resistant hypertension, especially monotherapy.. Achieving adequate blood pressure control and reducing the risk of CVD complications can only be achieved with combinations of medications. A post hoc analysis showed that over 12 weeks of treatment, the Z/HCT 30/12.5 mg combination significantly reduced the risk of CVD complications over the next 10 years (Heart Score) in terms of reducing systolic and diastolic blood pressure compared to monotherapy with 30 mg of zofenopril (decreased by 1.9 and 0.2 percent, respectively), although at the beginning of the study, the risk in both groups did not differ statistically (7 vs. 9 percent). The treatment with Z/HCT 30/12.5 mg combination resulted in a greater reduction in CVD risk in higher-risk subgroups. The advantage of the Z/HCT 30/12.5 mg combination in reducing CVD risk compared to monotherapy with 30 mg of zofenopril remained even after 24 weeks of treatment. Therefore, the Z/HCT 30/12.5 mg combination more effectively reduced the CVD risk in individuals at higher risk.

Tolerance

Based on data from studies involving over 60 patients, like other ACE inhibitors, the Z/HCT 30/12.5 mg combination most commonly caused the following adverse effects: headache, dizziness, and dry cough. These adverse effects were mostly mild (64.3 percent of cases) or of moderate severity and were independent of patient age or gender. 9.9 percent of patients taking Z/HCT 30/12.5 mg reported noticeable adverse effects, and in 61.9 percent of cases, these adverse effects were confirmed to be related to the medication. Interestingly, the Z/HCT 30/12.5 mg combination less frequently caused adverse effects (no registered cases) than monotherapy with 30 mg/d zofenopril (3 percent) or Z60/HCT12.5 mg/d (12 percent). Only 1.7 percent of patients discontinued treatment with Z/HCT 30/12.5 mg. According to data from two comparative studies, Z/HCT 30/12.5 mg was as well-tolerated as monotherapy with 30 mg of zofenopril. The higher antihypertensive efficacy of Z/HCT 30/12.5 mg was not associated with a higher incidence of side effects such as reflex tachycardia. Patients discontinued treatment with the Z/HCT 30/12.5 mg combination even less frequently than those treated with monotherapy with 30 mg of zofenopril (6 and 11 percent, respectively). The rate of non-response cases did not differ between the two groups (2 percent). Treatment was discontinued due to adverse side effects by 4 percent of patients receiving monotherapy with 30 mg of zofenopril and 2 percent of patients receiving the Z/HCT 30/12.5 mg combination. In summary, patients with arterial hypertension tolerated the Z/HCT 30/12.5 mg combination as well as monotherapy with 30 mg of zofenopril. The tolerability of treatment was not dependent on the patients' metabolic profile.

Conclusions:

•    The Z/HCT 30/12.5 mg combination has a strong antihypertensive effect; •    The Z/HCT 30/12.5 mg combination normalizes blood pressure in a larger proportion of hypertensive patients than monotherapy with 30 mg of zofenopril; •    The Z/HCT 30/12.5 mg effectively reduces blood pressure in high CVD risk patients, i.e., those who should start hypertension treatment with a combination of medications; •    Patients with hypertension tolerated the Z/HCT 30/12.5 mg combination.tolerates as well as monotherapy with 30 mg of zofenopril, and tolerability is not dependent on patients' metabolic profile; •  Doctors primarily recommend the Z/HCT 30/12.5 mg combination for patients who don't see good blood pressure control with 30 mg of zofenopril monotherapy and for those at high cardiovascular risk requiring rapid, intensive hypertension treatment. Current studies are exploring the effect of the Z/HCT 30/12.5 mg combination on left ventricular mass, kidney function (microalbuminuria), and blood vessels (primarily the carotid artery's intima/media thickness and plaque size)—especially in the context of ineffective monotherapy with 30 mg of zofenopril. Researchers are also analyzing other organoprotective properties of Z/HCT 30/12.5 mg. According to "Zofenopril Plus Hydrochlorthiazide Fixed Combination in the Treatment of Hypertension and Associated Clinical Conditions. Cardiovascular Therapeutics 27 (2009) 275-288, prepared by Dr. J. Kastys"