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Abstract

Cardiovascular diseases are the leading cause of death worldwide. Risk factors are rarely seen individually, and the 2 most common and most frequently associated risk factors are hypertension and dyslipidemia (DL). Studies conducted in different parts of the world uniquely point out insufficient efficacy of hypertension and DL treatment, which is reflected in blood pressure and low-density lipoprotein levels higher than target values. A reason of this therapeutic failure is the reduced adherence, which is mainly caused by multidrug therapy. A possible solution for this problem is the use of fixed combinations. The main advantages of amlodipine/atorvastatin fixed combination are synergistic effect of these 2 components, a single-dose treatment, high safety profile, and good tolerance.

Keywords

amlodipine/atorvastatin cardiovascular disease fixed combination hypertension dyslipidemia

Introduction

Cardiovascular diseases (CVDs) are multifactorial processes that represent the leading cause of death in the developed countries.¹ The strongest predictors for CVD development are arterial hypertension (AH), dyslipidemia (DL), diabetes mellitus, cigarette smoking, and obesity, which are rarely seen in isolation. In most patients, a combination of risk factors is found to contribute and increase global cardiovascular risk. The AH and DL are one of the most common combination of risk factors.

According to the Multinational MONItoring of trends and determinants in CArdiovascular disease (MONICA) study, 35% of the Western Europe citizens have at least 2 CVD risk factors,² whereas the Framingham study demonstrated that 78% of men and 82% of women with hypertension had at least 1 associated risk factor.³ In the United Kingdom, 9.2 million people, 20% of adults, have AH and DL at the same time.⁴

Mechanisms of the Combined Effects of AH and Hypercholesterolemia in the Development of Atherosclerosis

The mechanisms of mutual interaction between AH and DL as well as their impact on target organs damage have not been adequately studied. It is assumed that the basis of this relationship is genetic or metabolic.⁵ The concomitant presence of AH and DL has a multiplicative rather than an additive effect on the development of atherosclerosis.

The adverse effects of AH and DL combined mostly affect the endothelium.⁶ The endothelial response to AH and DL includes inflammation with increased free-radical production, impaired vasomotor function, platelet and leukocyte adhesion to endothelial cells, and endothelial barrier dysfunction. Imbalance in free-radical production in endothelial cells may result in oxidative modification of cellular components, impaired cell function, and/or cellular apoptosis or necrosis.

Oxidative activation of enzymes (phospholipase A2), which accompanies the free-radical excess in AH and DL, could result in increased synthesis of lipids (platelet activation factor and leukotrienes) and proteins (adhesion molecules and cytokines), which further promotes inflammation. Oxidative stress in the vessel wall is accompanied by increased production of superoxide that is responsible for inactivation of nitrogen (II) oxide (NO), a powerful vasodilator. The production of free radicals is amplified by different enzymatic systems (nicotinamide adenine dinucleotide phosphate [NADPH] oxidase, xanthine oxidase, and mitochondrial enzymes) and angiotensin II (AT-II), which are very active in AH.

The prohypertensive effect of superoxide could be explained by NO inactivation or by indirectly promoting the vasoconstrictor production such as endothelin. On the other hand, in AH, activation of endothelial and leukocyte NADPH oxidase increases free radicals, and enzyme activity has been associated with activation of AT-1 receptors and cytokines (tumor necrosis factor α) that originate from circulating immune cells. Hypercholesterolemia is also responsible for the increase in free radicals and inflammation and reduction in NO synthase activity.

Reduced NO bioactivity in AH and DL has an important role in the development of vasomotor dysfunction. Increased leukocyte–endothelial adhesion, as well as increased vascular permeability that is responsible for endothelial dysfunction, was found essential in AH and DL. Additionally, these 2 conditions are characterized by enhanced platelet aggregation, changes in megakaryopoesis, abnormal coagulation factors, platelet activation, and fibrinolysis. On the other hand, an increase in blood pressure leads to distension of the arterial vessel wall, which facilitates the penetration and retention of potentially atherogenic lipoproteins in the arterial wall⁷ and could potentially explain why men with borderline AH had significant oxidation of low-density lipoprotein (LDL) particles and intima–media thickening compared with normotensive men.⁸

The adverse effect of DL on blood pressure level reflects on the influence of hypercholesterolemia on transport activity of ion channels, with reduced sodium efflux seen across the membrane of renal cells. In addition, increased cholesterol content of the cell membrane affects calcium transport by increasing the activity of L-type channels and influx of calcium into the smooth muscle cells.⁹ Table 1 illustrates the mechanisms of antiatherosclerotic and antihypertensive effects of amlodipine and atorvastatin as well as combined effects of combination therapy.

Table 1.

Antiatherosclerotic Effects of Amlodipine and Antihypertensive Effects of Atorvastatin.

Antiatherosclerotic effects of amlodipine

Inhibition of smooth muscle cell proliferation

Inhibition of platelets and leukocytes adhesion to endothelial surface

Inhibition of lipid peroxidation

Modulation of extracellular matrix metabolism

Endothelial cell cytoprotection

Enhancement of nitric oxide production

Restoration of surface-charge properties of modified LDL

Antihypertensive effects of atorvastatin

Increased sodium efflux across the membrane of renal cells

Decreased activity of L-type channels

Reduced influx of calcium into smooth muscle cells

Effects of combine therapy with amlodipine and statin

Improvement in nitric oxide release

Reduction in inflammation markers

Improvement in fibrinolytic balance

Decreased plasminogen activator inhibitor plasma levels

Increased tissue plasminogen activator activity

Decreased atherosclerotic plaque size and calcification

Normalization atherosclerotic plaque protein secretion profile

Improved vascular compliance

Decreased left ventricular mass index

Decreased carotid systolic BP

Improved insulin sensitivity

Abbreviations: BP, blood pressure; LDL, low-density lipoprotein.

Atorvastatin and Amlodipine: Therapy of Hypertension and DL

Hypertension and DL often remain inadequately controlled despite the numerous possible therapies for both the entities.¹⁰ The EUROASPIRE III survey study conducted in 12 European countries showed that a satisfactory reduction in arterial blood pressure (<140/90 mm Hg) was achieved in only 26% of the patients and reduction in LDL (<2.5 mmol/L) in 31%.¹¹

The efficacy of fixed combinations was confirmed by several studies^12–18 (Table 2). In the Glycemic Effect in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensives (GEMINI) study, nearly 60% of all the patients and more than 75% without CVD and/or coronary artery disease (CAD) reached a target value of arterial blood pressure and LDL after 14 weeks of treatment with a fixed combination of amlodipine and atorvastatin.¹⁴ However, the reductions in arterial blood pressure and LDL were more significant in patients without CAD or diabetes mellitus. The target values were achieved only in 37% of the patients with CAD, although in more than 70% of the patients 1 of the 2 goals was achieved. In the GEMINI Australia, Asia, Latin America, Africa/Middle East (AALA) study, the LDL target goal was achieved in 87% of the patients with a fixed combination of amlodipine and atorvastatin.²² In the GEMINI¹⁴ and GEMINI-AALA²² trials, the mean blood pressure was reduced from baseline by 17.1/9.6 mm Hg¹⁴ and 20.2/11.4 mm Hg,²² and the mean reduction in LDL cholesterol (LDL-C) was 32.7%¹⁴ and 28.6%.²²

Table 2.

Results of Trials of Amlodipine and Atorvastatin Combination.

Study	No. of Patients	Baseline Value SPB/DBP, mm Hg	Baseline Value LDL-C, mmol/L	Patients Achieving BP and LDL-C Goals, %	Patients Achieving BP Goals, %^a	Patients Achieving LDL Goals, %^b
AVALON¹⁹	847	147/92	4.25	67.1	51	82.1
CAPABLE¹⁶	499	147/91	3.68	48.3	56.8	73.7
CRUCIAL²⁰	1461	150/90	3.64	50	58	83
CUSP²¹	63	147/91	3.44	47.6	65.1	74.6
GEMINI¹⁴	1220	146/88	3.96	57.7	65.5	74.7
GEMINI-AALA²²	1649	146/88	3.4	55.2	61.3	87.1
IMPACT²³	62	156/89	3	48.7	65.8	85.3
JAWEL I¹⁵	1138	152/90	5	62.9	66.8	90.7
JAWEL II¹⁵	1107	152/90	5	50.6	65.7	73.1
TOGETHER²⁴	244	132/81	3.39	67.8	79.9	84

Abbreviations: DBP, diastolic blood pressure; LDL-C, low-density lipoprotein cholesterol; SBP, systolic blood pressure.

^aTreatment goals for BP in the AVALON and CUSP studies were defined according to the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 6),²⁵ in the CAPABLE, CRUCIAL, and IMPACT studies according to the JNC 7,²⁶ in the JAWEL study according to the European, Canadian, and UK guidelines; and in the CUSP and TOGETHER studies BP goal was <140/90 mm Hg.

^bTreatment goals for LDL-C levels in all the studies, except in the CUSP and TOGETHER studies, were defined according to the National Cholesterol Education Program Adult Treatment Panel III.²⁷ Only in the CUSP and TOGETHER studies, LDL-C goal was <100 mg/dL (2.6 mmol/L) for all the participants.

The JEWEL program (I and II) included 2219 patients, 1135 from the United Kingdom and Canada (I) and 1034 from 8 European countries (II) with AH and DL.¹⁵ The mean blood pressure reduction from baseline was 20.4/10.7 mm Hg for JEWEL I and 21.8/12.6 mm Hg for JEWEL II. In program I, the target value of blood pressure and LDL was achieved in 62.9% of the patients, whereas in program II, this goal was reached in 50.6% of the patients.

The CAPABLE study in African Americans revealed satisfactory control of arterial blood pressure and cholesterol levels in 48.3% of the patients.¹⁶ The subanalysis of efficacy of a fixed combination of amlodipine/atorvastatin in a group of patients with metabolic syndrome and/or diabetes mellitus showed less improvement in arterial blood pressure values in the group of patients with metabolic syndrome than in those with only diabetes mellitus (38.5% vs 48.5%).¹⁷ The target level of LDL was achieved in about 60% of the patients due to atorvastatin subdosing both in the group of patients with diabetes and with the metabolic syndrome.

The results of the CUSP and TOGETHER studies also showed that the fixed combination of amlodipine/atorvastatin with lifestyle modification achieves satisfactory reduction in cardiovascular risk in patients with AH and DL.^21,24 In the CUSP trial, significantly more patients treated with amlodipine/atorvastatin reached both BP and LDL-C goals in comparison with placebo at week 4 (47.6% vs 1.7%) and at week 8 (55.6% vs 5.0%).²¹ The CUSP study showed that the 10-year Framingham risk of CHD was reduced by 33% and 38% in patients who received amlodipine/atorvastatin combination at weeks 4 and 8, whereas patients receiving placebo showed an increased risk of 4.1% at both the time points. The TOGETHER trial reported that the amplodipine/atorvastatin regimen with lifestyle changes reached both BP and LDL-C goals in 67.8% of the patients after 6 weeks of therapy and in only 9.8% of patients who were treated only with amlodipine.²⁰

The IMPACT study demonstrated that the use of the fixed combination of amlodipine/atorvastatin in combination with other antihypertensive agents led to significant improvement in blood pressure control (from 35% to 43.5% reduction) after a 6-month examination and hypercholesterolemia (from 21.5% to 56.4% reduction).²³

The CRUCIAL study results support a proactive correction of risk factors.²² The study included patients with AH, moderately elevated levels of total cholesterol (≤6.5 mmol/L), and with at least 3 more risk factors. Blood pressure goals were achieved to a slightly greater extent in the proactive intervention (amlodipine/atorvastatin) versus the usual care arm at week 16 (49% vs 46%), and this increased to 58% versus 48% (P < .001) at week 52. The LDL goals were achieved to a much greater extent in the proactive intervention versus the usual care arm at both week 16 (88% vs 53%; P < .001) and week 52 (83% vs 53%; P < .001). Dual blood pressure/LDL-C goal attainment was also achieved in a significantly higher proportion of patients in the proactive intervention using amlodipine/atorvastatin regimen versus the usual care arm at both week 16 (43% vs 26%; P < .001) and week 52 (50% vs 27%; P < .001). Proactive treatment significantly reduced the risk of CAD after 12 months (estimated by the Framingham score) compared to the standard treatment (33% vs 4%). In the proactive group of patients, a 24% reduction in the rise of fatal CVD (36% vs 12%) was observed.

Atorvastatin and Amlodipine: Prevention of CVD

Modification of lifestyle is an integral part of the treatment of AH and DL.¹⁰ However, benefits from the isolated lifestyle modification are modest and insufficient in most patients, which is why medical treatment is needed. The Anglo-Scandinavian Cardiac Outcomes Trail–Lipid Lowering Arm (ASCOT-LLA) study represents the cornerstone of evidence about the importance of correcting the 2 most common risk factors (AH and DL) in the primary prevention of CVD²⁸ (Table 3). This study included 10 305 patients with hypertension with at least 3 CV risk factors but without previous myocardial infarction (MI), angina, or heart failure. Patients were randomized to receive atorvastatin or placebo in addition to their antihypertensive (amlodipine-based or atenolol-based therapy). Atorvastatin with amlodipine-based therapy significantly reduced CV events in patients with hypertension in comparison with atenolol-based therapy.²⁸ The trial was stopped earlier (after 3.3 years) because of the proven benefits from atorvastatin in the prevention of nonfatal MI and fatal coronary artery heart disease (36% risk reduction). Further analyses of the results showed that atorvastatin compared with placebo reduced the incidence of nonfatal MI and CAD by 53% in amlodipine-based therapy in comparison with 16% in atenolol-based therapy (Table 3).

Table 3.

Effects of atorvastatin versus placebo in ASCOT-LLA and ASCOT-BPLA study^24,25.

Endpoint	HR (95%CI)
	ASCOT-LLA Atorvastatin vs. placebo	ASCOT-BPLA Amlodipine vs. atenolol
	(3.3 years)	(5.5 years)
Total coronary events	0.71 (0.59-0.86) ‡	0.84 (0.78-0.90)* ‡
Total cardiovascular events	0.79 (0.69-0.90) ‡	0.84 (0.78-0.90)* ‡
Fatal and non-fatal stroke	0.73 (0.56-0. 96) †	0.77 (0.66-0.89) ‡

†-p<0.05, ‡<0.01,*- total cardiovascular and coronary events.

The Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA) was the arm of ASCOT-LLA trial conducted for a total of 5.5 years²⁹ and confirmed the previously shown benefit of atorvastatin therapy.²⁸ Thus, the rate of the primary end point was reduced by 46% in the amlodipine-based regimen and by 25% in the atenolol-based regimen (Table 3).

Clunn et al have tried to explain the advantage of a concomitant treatment with a calcium channel blocker and statin in an in vitro model.³⁰ The administration of amlodipine and atorvastatin in the same time induced a synergistic dose-dependent increase in NO as well as improvement in vascular wall compliance and insulin resistance. This was confirmed by the AVALON-AWC trial that included patients with AH and DL in whom amlodipine led to the improvement in small artery compliance compared with placebo.³⁰ Adding atorvastatin to the therapy had a more favorable effect.³⁰

A possibility to Overcome Problems in the Treatment of Hypertension and Hypercholesterolemia

One possible reason for poor lipid and blood pressure control is the low level of adherence to medications. Possible reasons for the low level of adherence include female gender, age (<45 and >75 years), poor socioeconomic status, dementia, depression, discouragement of patients who had an acute MI despite the treatment of AH and DL, well-being, taking multiple drugs in multiple daily doses, and drug cost.³¹ There are numerous ways to improve adherence. One of the easiest is to use drugs in fixed combinations. Compared with a single-drug formulation of 2 different drugs, a fixed combination improves drug compliance, enhances drug adherence, and reduces treatment costs.

Results of several studies have shown that the use of fixed combinations improves the level of therapy adherence in AH and DL.^1,12 Patel et al compared the level of adherence in the treatment of AH and DL with the application of the fixed combination of amlodipine/atorvastatin with individually applied calcium channel blockers and other statin, including amlodipine and atorvastatin.¹³ They found that adherence with the usage of fixed combinations was almost 2-fold higher than the application of amlodipine and atorvastatin alone (odds ratio 1.95) and 2.06- to 3.10-fold higher than other statin and calcium channel blocker.¹³

Chapman et al have shown that the 6-month adherence in patients who received a fixed combination of amlodipine/atorvastatin was better than when these drugs were taken separately (56.5% vs 21.4%) and was associated with a lower risk of cardiovascular events in primary prevention.¹

The profile of side effects in the proactive regimen was the same as in the AVALON RISPONDI studies.^19,25 In the AVALON study, the frequency of drug discontinuation due to side effects was 7.7% for the combination of amlodipine/atorvastatin, 7.0% for amlodipine therapy alone, 7.5% for atorvastatin alone, and 9.6% for placebo.¹⁹ Side effects were still more common with the combination of amlodipine/atorvastatin than placebo (5.3% vs 2.1%). The most often reported side effects were peripheral edema, myalgia, and sinusitis. In the RESPOND study, the side effects with the use of the combination of amlodipine/atorvastatin were similar to those experienced when taking the individual components.³²

Conclusion

Despite the numerous therapies available for AH and DL, their correction is far from optimal. One of the possible reasons may be the reduced acceptance of treatment, which can be partially corrected using fixed combinations. So far, the first fixed combination applied in the treatment of these 2 risk factors is the combination of amlodipine and atorvastatin. In addition to efficacy, which is based on the synergistic effect of both the components, the number of side effects was lower than with the application of the individual components. It is important to emphasize that this fixed combination has proven to be useful in patients with various levels of CVD risk. This fixed combination supports the polypill concept that is still in progress.

Footnotes

Declaration of Conflicting Interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Professor Ivanovic has been a consultant or has received travel expenses, or payment for speaking at meetings, from one or more pharmaceutical companies (including Pfizer, which manufacture single-pill amlodipine/atorvastatin) that market blood pressure-lowering or lipid-lowering drugs. Dr Tadic reported no conflict of interest.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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Fixed Combination of Amlodipine/Atorvastatin

Abstract

Keywords

Introduction

Mechanisms of the Combined Effects of AH and Hypercholesterolemia in the Development of Atherosclerosis

Atorvastatin and Amlodipine: Therapy of Hypertension and DL

Atorvastatin and Amlodipine: Prevention of CVD

A possibility to Overcome Problems in the Treatment of Hypertension and Hypercholesterolemia

Conclusion

Footnotes

Declaration of Conflicting Interests

Funding

References