In the heart of hypertension treatment: single-pill combinations containing a renin-angiotensin-aldosterone system blocker

    Authors

    Abstract

    Although the awareness and control of hypertension have increased, improved achievement rates for target blood pressure (BP) levels remain an unmet need worldwide. Due to a multifactorial etiology of hypertension, BP targets cannot be reached with a single agent in most patients. Low adherence to antihypertensive treatment, which is in direct correlation with the number of medications prescribed, has been recognized as a major contributor to poor BP control. The need to improve BP control is reflected in the 2018 ESC/ESH Guidelines for the management of arterial hypertension, which developed a simple and pragmatic treatment strategy for a more effective and faster lowering of BP to target levels – the most important issue in the management of hypertension.

    Keywords

    target blood pressure, adherence, guidelines, combination therapy, single-pill combination

    DOI

    https://doi.org/10.15836/ccar2018.526

    Full Text

    ## Introduction High blood pressure (BP) is an important global health challenge due to its high prevalence and resulting cardiovascular (CV) and chronic kidney disease. ( 1 ) To provide an insight into the global trends in high BP, investigators brought together data from 844 population-based studies conducted in 154 countries from 1990 to 2015. One of the key findings was that the number of people with systolic blood pressure (SBP) of 140 mmHg or higher was estimated to have increased from 442 million in 1990 to 874 million in 2015. ( 2 ) The number of people with high BP will continue to rise in the future due to population ageing and an unhealthy lifestyle. ( 3 ) Hypertension is the leading preventable risk factor for premature death and disability worldwide, but despite some improvements, BP control remains an unmet goal. ( 1 , 4 ) As shown by recent observations, irrespective of the world region, whether high- or low-income economies, only approximately 40% of patients with hypertension are treated; of these, only approximately 35% are controlled to a BP of 140/90 mmHg or lower. This is a major missed opportunity for CV disease prevention in millions of people across the world. ( 4 ) Achieving optimal BP control is the most important single concern in the management of hypertension, and in most hypertensive patients, it is difficult or impossible to control BP with a single medicine. For example, in the large Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack (ALLHAT) trial, less than 30% of more than 42,000 participants achieved BP targets (below 140/90 mmHg) on monotherapy. ( 5 ) Based on the evidence from recent large meta-analyses of randomized controlled trials (RCTs), which have provided strong support for more aggressive BP lowering (SBP below 130 mmHg) in terms of reducing the risk of major CV events, the 2018 ESC/ESH Guidelines for the management of arterial hypertension set target BP ranges in treated patients. The guidelines recommend that when BP lowering drugs are used, the first objective should be to lower BP below 140/90 mmHg in all patients. If the treatment is well-tolerated, treated BP should be targeted to 130/80 mmHg or lower in most patients. In patients older than 65 years SBP should be between 130 and 140 mmHg and diastolic blood pressure (DBP) 80 mmHg or lower. Treated SBP should not be targeted to 120 mmHg or lower. In the context of new BP thresholds and the necessity to improve BP control, the guidelines developed an evidence-based treatment algorithm for more effective and faster achievement of BP targets. Among key recommendations is initiation of therapy with a combination in a majority of hypertensive patients, and the preference of single-pill combinations (SPCs), as they improve adherence, which has a determinant role in achieving therapeutic goals. ( 4 ) In the context of new BP thresholds and the necessity to improve BP control, the guidelines developed an evidence-based treatment algorithm for more effective and faster achievement of BP targets. Among key recommendations is initiation of therapy with a combination in a majority of hypertensive patients, and the preference of single-pill combinations (SPCs), as they improve adherence, which has a determinant role in achieving therapeutic goals. ( 4 ) ## Two-drug combination – first-line treatment for the majority of patients The current data suggest that at least three quarters of hypertensive patients require combination therapy to achieve BP targets. ( 6 ) In light of new guidelines, emphasizing the importance of reducing BP to 120-129 mmHg in most patients, this proportion might be even bigger. From this viewpoint the new guidelines suggest a two-drug combination as the first-line treatment strategy in the majority of patients. Due to the benefits demonstrated in large event-based RTCs, the guidelines favor the use of a two-drug combination of a renin-angiotensin-aldosterone system (RAAS) blocker and a calcium channel blocker (CCB) or diuretic as the preferred classes of antihypertensives ( Figure 1 ). Monotherapy should now be considered only in low-risk patients with grade 1 hypertension (SBP up to 150 mmHg), patients with high-normal BP and established CV disease or in very old or frail patients. ( 4 ) Core medication treatment strategy for uncomplicated hypertension according to 2018 European Society of Cardiology/European Society of Hypertension Guidelines for the Management of Arterial Hypertension. ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; CCB = calcium-channel blocker; HMOD = hypertension-mediated organ damage; o.d. = omni die (every day); PAD = peripheral artery disease. What is the most important rationale for using combination therapy in clinical practice? Hypertension is multifactorial and since many pathophysiologic factors contribute to high BP, a combination of agents with different mechanisms of action provides more complete blockade of pressor mechanisms with less activation of counter-regulatory mechanisms. ( 5 ) By combining two agents with complementary mechanisms of action, an antihypertensive effect of two to five times greater than that obtained by monotherapy is possible. ( 7 ) Combination therapy also improves tolerability by reducing dose-dependent adverse reactions (clinical or metabolic) of individual components. Upward dose titration in an attempt to avoid the addition of a second agent often leads to increases in dose-dependent adverse reactions, resulting in discontinuation of therapy. Appropriate combination therapy can also improve tolerability if one component can neutralize the adverse reactions of the second agent. ( 5 ) Furthermore, the studies from large hypertension cohorts in usual care have shown that initial combination treatment results in reduced treatment discontinuations and a lower risk of CV events than initial monotherapy followed by the traditional stepped-care approach. ( 4 ) Increasing the dose of monotherapy reduces coronary events by 29% and cerebrovascular events by 40%, while the initial combination reduces them by 40% and 54%, respectively. ( 7 ) ## Single-pill combinations for better adherence, the key to therapeutic success Low adherence to treatments for chronic diseases is a global problem. ( 8 ) A survey showed that one-third of patients receive at least two prescriptions and 10% of patients receive four or more prescriptions on a visit to a primary care physician. ( 5 ) Low adherence is of particular concern in hypertension, with about half of the patients prescribed an antihypertensive drug stopping taking it within one year. ( 8 ) The collected data demonstrate that low adherence is the major cause of poor BP control, unequivocally being directly affected by the number of pills and complexity of treatment regimen. ( 4 , 5 ) A recent study showed that non-adherence was usually less than 10% with a single pill, rising to approximately 20% with two pills, approximately 40% with three pills, and very high rates of partial or complete non-adherence in patients receiving five or more pills. ( 4 ) The essential need for simple-to-follow and pragmatic treatment regimens is also highlighted in the new guidelines. They suggest the use of SPCs whenever applicable because they simplify medication taking, significantly improve medication adherence and increase the rate of BP control, which is the basic prerequisite for reducing the risk of CV events – the ultimate goal of hypertension treatment. ( 4 , 8 ) Krka’s single-pill combinations containing renin-angiotensin-aldosterone system blocker – an effective, safe and simple choice for any hypertensive patient It is 30 years since Krka introduced enalapril (Enap ® ), which had long been the gold standard in the treatment of hypertension. ( 9 ) Since then, new and improved medicines have continuously been added to Krka’s RAAS portfolio. Krka is today one of the leading global RAAS blocker producers with 21 SPCs containing a RAAS blocker (11 SPCs with a diuretic, eight SPCs with a CCB and two triple SPCs with a CCB and a diuretic), which enable individually-tailored treatment of more than 11 million hypertensive patients. In Croatia there are 20 Krka’s RAAS products available, among which 12 are SPCs. ( 10 ) In 2011 Krka introduced perindopril (Perineva ® ) and a SPC containing the metabolically neutral diuretic indapamide (Co-Perineva ® ) to Croatia, where this molecule had earlier not been widely used. ( 11 ) The Croatian professionals accepted perindopril as a step forward in the hypertension treatment, since perindopril exerts benefits (gradual onset of action and 24-hour BP normalization, advantageous pleiotropic properties translated into better organ protection and improved outcomes, as well as a favorable safety profile), which are not observed with any other ACE inhibitor. ( 12 ) The potential of perindopril has been widely recognized in the clinical settings, making it one of the preferred ACE inhibitors in Croatia today. This is in parallel with the prescription habits of physicians in a big part of Europe. ( 10 ) Krka’s perindopril is produced in the form of erbumine salt, considered as the proven classic perindopril. All major perindopril clinical studies with morbidity and mortality endpoints, which included more than 55,000 patients, and which were the basis for wide use of perindopril in clinical practice, were conducted with perindopril erbumine. ( 13 - 18 ) In 2012 Krka introduced a SPC of perindopril and amlodipine (Dalneva ® ), one of the most favored combinations in the treatment of hypertension. ( 10 , 19 ) Krka’s single-pill combination of perindopril, amlodipine and indapamide – a simple therapeutic approach for patients who need three-drug combination therapy Studies suggest that two-drug combination therapy will control BP in approximately two-thirds of patients. For patients whose BP is not adequately controlled by two-drug combination therapy, the logical continuation is the upgrade of treatment to three-drug combination therapy. This approach is supported by the guidelines, suggesting a RAAS blocker, a CCB and a diuretic as the preferred components of three-drug combinations, ideally in a SPC. ( 4 ) Already in 2013 Krka registered a triple SPC of perindopril, amlodipine and indapamide as the first company to offer such a combination in Europe. ( 20 ) In Croatia Krka’s triple SPC of perindopril, amlodipine and indapamide (Co-Dalneva ® ) was introduced in 2018 and it possesses all the qualities of other Krka’s perindopril products. Co-Dalneva is registered as the new SPC of the approved active substances. ( 21 - 23 ) Triple SPC is a simple solution for the most demanding hypertension cases. ( 4 ) Recently, an open-label prospective study with Co-Dalneva ® was published. The study included 44 patients with arterial hypertension and at high and very high risk of CV events who did not achieve their BP targets with the previous combined therapy (double free/single-pill or triple free combination). BP levels, the level of adherence to treatment, biochemical parameters, levels of inflammation markers (CRP, IL-6, IL-10) and endothelial dysfunction (sVCAM-1, VEGF) were assessed in all patients at baseline and after six months of therapy. A month after initiating the triple SPC of perindopril, amlodipine and indapamide, 47.7% of the patients achieved their target BP levels, rising to 93% of the patients after 3 months of therapy. By the end of the study all the patients had target BP levels ( Figure 2 ). Pulse BP, which reflects arterial elasticity, was reduced significantly during therapy (by 30.3 mmHg). The treatment was associated with substantially improved level of adherence – the percentage of non-adherent patients decreased from 86.4% at baseline to only 4.5% at the end of the treatment. No significant changes of biochemical parameters and markers of inflammation were observed. The levels of sVCAM-1 significantly decreased (from 1063.5±442.4 to 898.67±433.5 ng/mL). The study demonstrated effective lowering of BP to target levels and reduction of pulse BP, increase in adherence level, good tolerability and metabolic neutrality as well as improved vascular endothelial function. ( 24 ) Significant reduction of systolic blood pressure (SBP) and diastolic blood pressure (DBP) after the first month of treatment with Krka’s SPC of perindopril, amlodipine and indapamide, and target blood pressure levels with a mean SBP of 125.1 mmHg and a mean DBP of 82.2 mmHg after 6 months. ## Conclusion Hypertension is the most common risk factor for CV death and disability in both developed and developing countries and control of BP significantly reduces these risks. ( 5 ) Despite the efforts to improve BP control, still less than 40% of treated patients achieve the recommended BP targets. Among the main reasons for low BP control rates are the high number of undiagnosed hypertensive patients, suboptimal treatment regimens (monotherapy can effectively reduce BP in a minority of patients) and non-adherence as the most frequent cause of failure to achieve BP goals in treated patients. The latest guidelines offered solutions for more effective and faster achievement of BP targets to improve the global picture of CV diseases as a dominant cause of death. ( 4 ) Krka with its complex perindopril portfolio in numerous combinations and strengths enables a high-quality hypertension treatment according to the latest guideline recommendations. ( 4 , 10 )

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    In the heart of hypertension treatment: single-pill combinations containing a renin-angiotensin-aldosterone system blocker

    Professional Article
    Issue11-12
    Published
    Pages526-531
    PDF via DOIhttps://doi.org/10.15836/ccar2018.526
    target blood pressure
    adherence
    guidelines
    combination therapy
    single-pill combination

    Authors

    Teja PrijateljORCIDSlovenia
    Breda Barbič-Žagar*ORCIDSlovenia

    Abstract

    Although the awareness and control of hypertension have increased, improved achievement rates for target blood pressure (BP) levels remain an unmet need worldwide. Due to a multifactorial etiology of hypertension, BP targets cannot be reached with a single agent in most patients. Low adherence to antihypertensive treatment, which is in direct correlation with the number of medications prescribed, has been recognized as a major contributor to poor BP control. The need to improve BP control is reflected in the 2018 ESC/ESH Guidelines for the management of arterial hypertension, which developed a simple and pragmatic treatment strategy for a more effective and faster lowering of BP to target levels – the most important issue in the management of hypertension.

    Full Text

    ## Introduction High blood pressure (BP) is an important global health challenge due to its high prevalence and resulting cardiovascular (CV) and chronic kidney disease. ( 1 ) To provide an insight into the global trends in high BP, investigators brought together data from 844 population-based studies conducted in 154 countries from 1990 to 2015. One of the key findings was that the number of people with systolic blood pressure (SBP) of 140 mmHg or higher was estimated to have increased from 442 million in 1990 to 874 million in 2015. ( 2 ) The number of people with high BP will continue to rise in the future due to population ageing and an unhealthy lifestyle. ( 3 ) Hypertension is the leading preventable risk factor for premature death and disability worldwide, but despite some improvements, BP control remains an unmet goal. ( 1 , 4 ) As shown by recent observations, irrespective of the world region, whether high- or low-income economies, only approximately 40% of patients with hypertension are treated; of these, only approximately 35% are controlled to a BP of 140/90 mmHg or lower. This is a major missed opportunity for CV disease prevention in millions of people across the world. ( 4 ) Achieving optimal BP control is the most important single concern in the management of hypertension, and in most hypertensive patients, it is difficult or impossible to control BP with a single medicine. For example, in the large Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack (ALLHAT) trial, less than 30% of more than 42,000 participants achieved BP targets (below 140/90 mmHg) on monotherapy. ( 5 ) Based on the evidence from recent large meta-analyses of randomized controlled trials (RCTs), which have provided strong support for more aggressive BP lowering (SBP below 130 mmHg) in terms of reducing the risk of major CV events, the 2018 ESC/ESH Guidelines for the management of arterial hypertension set target BP ranges in treated patients. The guidelines recommend that when BP lowering drugs are used, the first objective should be to lower BP below 140/90 mmHg in all patients. If the treatment is well-tolerated, treated BP should be targeted to 130/80 mmHg or lower in most patients. In patients older than 65 years SBP should be between 130 and 140 mmHg and diastolic blood pressure (DBP) 80 mmHg or lower. Treated SBP should not be targeted to 120 mmHg or lower. In the context of new BP thresholds and the necessity to improve BP control, the guidelines developed an evidence-based treatment algorithm for more effective and faster achievement of BP targets. Among key recommendations is initiation of therapy with a combination in a majority of hypertensive patients, and the preference of single-pill combinations (SPCs), as they improve adherence, which has a determinant role in achieving therapeutic goals. ( 4 ) In the context of new BP thresholds and the necessity to improve BP control, the guidelines developed an evidence-based treatment algorithm for more effective and faster achievement of BP targets. Among key recommendations is initiation of therapy with a combination in a majority of hypertensive patients, and the preference of single-pill combinations (SPCs), as they improve adherence, which has a determinant role in achieving therapeutic goals. ( 4 ) ## Two-drug combination – first-line treatment for the majority of patients The current data suggest that at least three quarters of hypertensive patients require combination therapy to achieve BP targets. ( 6 ) In light of new guidelines, emphasizing the importance of reducing BP to 120-129 mmHg in most patients, this proportion might be even bigger. From this viewpoint the new guidelines suggest a two-drug combination as the first-line treatment strategy in the majority of patients. Due to the benefits demonstrated in large event-based RTCs, the guidelines favor the use of a two-drug combination of a renin-angiotensin-aldosterone system (RAAS) blocker and a calcium channel blocker (CCB) or diuretic as the preferred classes of antihypertensives ( Figure 1 ). Monotherapy should now be considered only in low-risk patients with grade 1 hypertension (SBP up to 150 mmHg), patients with high-normal BP and established CV disease or in very old or frail patients. ( 4 ) Core medication treatment strategy for uncomplicated hypertension according to 2018 European Society of Cardiology/European Society of Hypertension Guidelines for the Management of Arterial Hypertension. ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; CCB = calcium-channel blocker; HMOD = hypertension-mediated organ damage; o.d. = omni die (every day); PAD = peripheral artery disease. What is the most important rationale for using combination therapy in clinical practice? Hypertension is multifactorial and since many pathophysiologic factors contribute to high BP, a combination of agents with different mechanisms of action provides more complete blockade of pressor mechanisms with less activation of counter-regulatory mechanisms. ( 5 ) By combining two agents with complementary mechanisms of action, an antihypertensive effect of two to five times greater than that obtained by monotherapy is possible. ( 7 ) Combination therapy also improves tolerability by reducing dose-dependent adverse reactions (clinical or metabolic) of individual components. Upward dose titration in an attempt to avoid the addition of a second agent often leads to increases in dose-dependent adverse reactions, resulting in discontinuation of therapy. Appropriate combination therapy can also improve tolerability if one component can neutralize the adverse reactions of the second agent. ( 5 ) Furthermore, the studies from large hypertension cohorts in usual care have shown that initial combination treatment results in reduced treatment discontinuations and a lower risk of CV events than initial monotherapy followed by the traditional stepped-care approach. ( 4 ) Increasing the dose of monotherapy reduces coronary events by 29% and cerebrovascular events by 40%, while the initial combination reduces them by 40% and 54%, respectively. ( 7 ) ## Single-pill combinations for better adherence, the key to therapeutic success Low adherence to treatments for chronic diseases is a global problem. ( 8 ) A survey showed that one-third of patients receive at least two prescriptions and 10% of patients receive four or more prescriptions on a visit to a primary care physician. ( 5 ) Low adherence is of particular concern in hypertension, with about half of the patients prescribed an antihypertensive drug stopping taking it within one year. ( 8 ) The collected data demonstrate that low adherence is the major cause of poor BP control, unequivocally being directly affected by the number of pills and complexity of treatment regimen. ( 4 , 5 ) A recent study showed that non-adherence was usually less than 10% with a single pill, rising to approximately 20% with two pills, approximately 40% with three pills, and very high rates of partial or complete non-adherence in patients receiving five or more pills. ( 4 ) The essential need for simple-to-follow and pragmatic treatment regimens is also highlighted in the new guidelines. They suggest the use of SPCs whenever applicable because they simplify medication taking, significantly improve medication adherence and increase the rate of BP control, which is the basic prerequisite for reducing the risk of CV events – the ultimate goal of hypertension treatment. ( 4 , 8 ) Krka’s single-pill combinations containing renin-angiotensin-aldosterone system blocker – an effective, safe and simple choice for any hypertensive patient It is 30 years since Krka introduced enalapril (Enap ® ), which had long been the gold standard in the treatment of hypertension. ( 9 ) Since then, new and improved medicines have continuously been added to Krka’s RAAS portfolio. Krka is today one of the leading global RAAS blocker producers with 21 SPCs containing a RAAS blocker (11 SPCs with a diuretic, eight SPCs with a CCB and two triple SPCs with a CCB and a diuretic), which enable individually-tailored treatment of more than 11 million hypertensive patients. In Croatia there are 20 Krka’s RAAS products available, among which 12 are SPCs. ( 10 ) In 2011 Krka introduced perindopril (Perineva ® ) and a SPC containing the metabolically neutral diuretic indapamide (Co-Perineva ® ) to Croatia, where this molecule had earlier not been widely used. ( 11 ) The Croatian professionals accepted perindopril as a step forward in the hypertension treatment, since perindopril exerts benefits (gradual onset of action and 24-hour BP normalization, advantageous pleiotropic properties translated into better organ protection and improved outcomes, as well as a favorable safety profile), which are not observed with any other ACE inhibitor. ( 12 ) The potential of perindopril has been widely recognized in the clinical settings, making it one of the preferred ACE inhibitors in Croatia today. This is in parallel with the prescription habits of physicians in a big part of Europe. ( 10 ) Krka’s perindopril is produced in the form of erbumine salt, considered as the proven classic perindopril. All major perindopril clinical studies with morbidity and mortality endpoints, which included more than 55,000 patients, and which were the basis for wide use of perindopril in clinical practice, were conducted with perindopril erbumine. ( 13 - 18 ) In 2012 Krka introduced a SPC of perindopril and amlodipine (Dalneva ® ), one of the most favored combinations in the treatment of hypertension. ( 10 , 19 ) Krka’s single-pill combination of perindopril, amlodipine and indapamide – a simple therapeutic approach for patients who need three-drug combination therapy Studies suggest that two-drug combination therapy will control BP in approximately two-thirds of patients. For patients whose BP is not adequately controlled by two-drug combination therapy, the logical continuation is the upgrade of treatment to three-drug combination therapy. This approach is supported by the guidelines, suggesting a RAAS blocker, a CCB and a diuretic as the preferred components of three-drug combinations, ideally in a SPC. ( 4 ) Already in 2013 Krka registered a triple SPC of perindopril, amlodipine and indapamide as the first company to offer such a combination in Europe. ( 20 ) In Croatia Krka’s triple SPC of perindopril, amlodipine and indapamide (Co-Dalneva ® ) was introduced in 2018 and it possesses all the qualities of other Krka’s perindopril products. Co-Dalneva is registered as the new SPC of the approved active substances. ( 21 - 23 ) Triple SPC is a simple solution for the most demanding hypertension cases. ( 4 ) Recently, an open-label prospective study with Co-Dalneva ® was published. The study included 44 patients with arterial hypertension and at high and very high risk of CV events who did not achieve their BP targets with the previous combined therapy (double free/single-pill or triple free combination). BP levels, the level of adherence to treatment, biochemical parameters, levels of inflammation markers (CRP, IL-6, IL-10) and endothelial dysfunction (sVCAM-1, VEGF) were assessed in all patients at baseline and after six months of therapy. A month after initiating the triple SPC of perindopril, amlodipine and indapamide, 47.7% of the patients achieved their target BP levels, rising to 93% of the patients after 3 months of therapy. By the end of the study all the patients had target BP levels ( Figure 2 ). Pulse BP, which reflects arterial elasticity, was reduced significantly during therapy (by 30.3 mmHg). The treatment was associated with substantially improved level of adherence – the percentage of non-adherent patients decreased from 86.4% at baseline to only 4.5% at the end of the treatment. No significant changes of biochemical parameters and markers of inflammation were observed. The levels of sVCAM-1 significantly decreased (from 1063.5±442.4 to 898.67±433.5 ng/mL). The study demonstrated effective lowering of BP to target levels and reduction of pulse BP, increase in adherence level, good tolerability and metabolic neutrality as well as improved vascular endothelial function. ( 24 ) Significant reduction of systolic blood pressure (SBP) and diastolic blood pressure (DBP) after the first month of treatment with Krka’s SPC of perindopril, amlodipine and indapamide, and target blood pressure levels with a mean SBP of 125.1 mmHg and a mean DBP of 82.2 mmHg after 6 months. ## Conclusion Hypertension is the most common risk factor for CV death and disability in both developed and developing countries and control of BP significantly reduces these risks. ( 5 ) Despite the efforts to improve BP control, still less than 40% of treated patients achieve the recommended BP targets. Among the main reasons for low BP control rates are the high number of undiagnosed hypertensive patients, suboptimal treatment regimens (monotherapy can effectively reduce BP in a minority of patients) and non-adherence as the most frequent cause of failure to achieve BP goals in treated patients. The latest guidelines offered solutions for more effective and faster achievement of BP targets to improve the global picture of CV diseases as a dominant cause of death. ( 4 ) Krka with its complex perindopril portfolio in numerous combinations and strengths enables a high-quality hypertension treatment according to the latest guideline recommendations. ( 4 , 10 )