Download 潒慳楬a - WebMedFamily.org

“Rosalia”
Effectiveness and safety of combined antihypertensive and cholesterolreducing therapy (lisinopril-amlodipine and rosuvastatin) in high and very
high risk patient populations
Introduction
Cardiovascular diseases are at the top of the mortality statistics both worldwide and in
Hungary. The WHO forecasts that over the next 10-year period cardiovascular diseases will
continue to feature as the leading cause of death (1). Following a diagnosis of cardiovascular
disease, modern therapy has the aim and task of slowing the progression of the atherosclerosis
and preventing the occurrence of repeated events. Secondary prevention through medication
rests on four main pillars: beta blockers, ACE inhibitors, lipid-reducing statins and
thrombocyte aggregation inhibitors. It has been known since 2002 that in secondary
prevention the prophylactic drugs, independently of each other, reduce the relative risk of
cardiovascular events by 25-30% (2). It was these factors that first suggested the rationale for
a polypill strategy. The studies of past years have aimed to define the target values of the
clinical parameters (blood pressure, blood lipids, heart frequency, efficacious thrombocyte
aggregation inhibition). In order to achieve the favourable mortality data, when applying any
of the four preventive products, the major clinical trials highlight in particular the necessity of
titration to reach the target values of the tested parameters (IDEAL, TNT, PROVE-IT TIMI,
ACCOMPLISH, HOT, CAPRIE, COMMIT, MacAlister, CIBIS-ELD, BEAUTIFUL, SHIFT)
(3-6).
For hypertensive patients blood pressure can be normalised using monotherapy in a
lower proportion of cases (approx. 30%), while for the vast majority of patients combination
antihypertensive therapy is needed. For patients with a high cardiovascular risk, based on the
data of the HOT, UKPDS, RENAAL study, to achieve the target blood pressure the combined
use of an average of 2 or more drugs was necessary. With the use of two active ingredients
that complement each other’s mechanism of effect, the antihypertensive effects are
compounded, or a potentiating synergy can arise, permitting successful titration of the blood
pressure to reach the target value. With regard to “treatment to target”, we have to point out
that the previous target values, valid in 2011, have changed considerably on the basis of the
2013 protocol. The introduction of less strict target values, however, does not substantively
alter the fact that approximately two thirds of hypertensive patients can only be made
normotensive with combination treatment. With regard to free-drug and fixed-dose
combinations, a further benefit of the latter, from the patient’s perspective, is the considerable
improvement in compliance that it brings (7, 8).
The combination of ACE-inhibitor and long-acting Ca-channel-blocker stands out
among combination antihypertensive treatment strategies by virtue of the target organ
protection (carotid intima-media thickness and left ventricular hypertrophy) that can be
demonstrated irrespective of blood pressure, in addition to the effective blood pressure control
(9-10). The ACCOMPLISH trial certified the beneficial effect of ACE-inhibitor and Cachannel-blocker combination therapy on the development of cardiovascular events in
hypertensive patients, as compared to the ACE-inhibitor diuretic combination, which was
observed alongside an identical reduction in blood pressure for both combination strategies
(6).
The protocols of the European and Hungarian Society of Hypertension recommend
combinations of ACE-inhibitors and Ca-channel-blockers as the first-line therapy for
hypertension. Lisinopril-amlodipine® is a fixed-dose combination of two long-acting agents
that are very similar in terms of their pharmacokinetic properties. The lisinopril-amlodipine®
combination containing 10 mg lisinopril and 5 mg amlodipine was authorised for the
treatment of hypertension in Hungary in 2004, while the 20/5 mg formulation was authorised
in 2012, and Lisinopril-amlodipine forte (20/10 mg) in 2009.
A Multiple Risk Factor Intervention Trial (MRFIT) proved in 1995 that an increase in
both systolic blood pressure and the total cholesterol level together leads to an exponential
increase in cardiovascular morbidity. Since then numerous controlled, randomised clinical
trials involving high case numbers have proven the effect of statins in reducing cardiovascular
events in both primary and secondary prevention (4S, LIPID, AFCAPS) (14-17). With
imaging tests (IVUS, CIMT) it was also proven that with a more than 50% decrease relative
to the starting LDL cholesterol level, not only the inhibition of progression in the
atherosclerotic plaques, (REVERSAL), but also a regression could be observed (ASTEROID)
(18, 19). In view of the above, the current international (ESC/EAS 2011) and domestic (5th
Hungarian Cardiovascular Consensus Conference) therapeutic protocols consider lipid
treatment to the target value to be necessary: in the case of high CV risk the LDL cholesterol
target value is <2.5 mmol/L, and for very high CV-risk patients <1.8 mmol/L, with at least a
50% reduction relative to the starting LDL cholesterol level. To achieve these strict targets,
however, effective and tolerable statin products are needed. The European guidelines
(ESC/EAS) published in July 2011 considerably broadened the range of very high CV risk
patients, thus necessitating the more widespread use of modern statin products in order to
achieve the target values (20). The ACC/AHA protocol issued in November 2013 resulted in
a paradigm shift. The main message of this protocol was that, based on a meta-analysis of the
multicenter trials, there is no evidence of the usefulness of treatment aimed at reaching the
target value. The new protocol does not recommend attaining the target value, but rather,
based on the percentage drop in the LDL-C value, it recommends medium (35-50%) or highly
effective (>50 LDL-C decrease) statin therapy depending on the patient’s risk status. This
novel approach provides a decision-making algorithm that is easier to use in everyday
practice. At the start of our present trial, however, determination of the trial protocol took
place on the 2011 European and domestic protocols that were still in effect at the time.
In Hungary, based on general-practice treatment data, the proportion of high CV-risk
patients attaining the LDL-cholesterol target value rose from 14% in 2004 to 40% in 2010
(CÉL 2004, Multi Gap 2010) (21). The extent of the increase is commendable in itself, as it
indicates the success of the awareness-raising campaign and the increasingly widespread use
of statins; however, 60% of the patients (and an even higher proportion in the case of very
high cardiovascular risk) are still not at the target value, which needs to be improved in the
light of the Hungarian cardiovascular mortality data.
Rosuvastatin is one of the most effective and tolerable statin products, and for the
majority of patients it facilitates the achievement of the LDL-cholesterol level target value in
the context of both primary and secondary prevention (STELLAR, MERCURY I) (22, 23).
With imaging tests (IVUS, CIMT) effective rosuvastatin treatment also resulted in regression
of the atherosclerotic plaque (ASTEROID, METEOR) (19, 24). In patients suffering from
acute coronary syndrome, 20 mg rosuvastatin brings about a similar reduction in further
cardiovascular events and the risk of mortality as a high, 80 mg dose of atorvastatin
(CENTAURUS) (25). In the STELLAR trial, with rosuvastatin treatment, not only was the
more effective attainment of the LDL-cholesterol target value proven, in comparison to
atorvastatin, simvastatin and pravastatin, but a significantly greater increase in the HDLcholesterol level was also observed (22). Rosuvastatin-containing, cost-effective generic
products have been available in Hungary since 2010.
The aim of the trial
The trial analyses the effectiveness and safety of lisinopril/amlodipine fixed-dose
combination antihypertensive drug therapy and cholesterol-reducing rosuvastatin free-drug
combination therapy, with the involvement of patients suffering from concomitant mild or
moderate hypertension and hypercholesterolemia with a high and very high cardiovascular
risk. Our trial is a 6-month, prospective observational noninterventional clinical trial (Ethical
Permit number: ETT TUKEB 8096-1/2012/EKU), with the aim of analysing what proportion
of the participating patients successfully reduce their initial above-target-value blood pressure
to the target value with fixed-dose lisinopril/amlodipine (10 mg/5 mg, 20 mg/5 mg, 20 mg/10
mg) combination therapy. With regard to the lipid profile we examine the proportion of
patients who previously did not achieve the target LDL-cholesterol value, but succeed in
attaining the target value with rosuvastatin (10 mg and 20 mg) therapy.
The secondary aim is to assess the safety and tolerability of concurrent lisinoprilamlodipine and rosuvastatin therapy. In the course of this we investigate the adverse events
(side effects) occurring following the start of the therapy, the incidence of such events, and
the proportion in which the side effects warrant suspension of the therapy.
Patients and methods
Patient selection
A total of 2,452 patients suffering from mild and moderate essential hypertension with
a high and very high cardiovascular risk were inducted into the trial at 256 testing centres,
where the examiners were doctors of internal medicine, cardiologists, hypertensionologists
and general practitioners. The prerequisites for participation in the trial were the following:
 over 18 years of age,
 mild (grade 1) or moderate (grade 2) hypertension, and the patient has not previously
received antihypertensive therapy or has been treated before but is not at the target
value: symptom-free, high cardiovascular risk hypertensive patient ≥140/90 Hgmm;
diabetes mellitus, metabolic syndrome, coronary and peripheral arterial disease
≥130/80 Hgmm; hypertensive patients aged over 79, ≥150/90 Hgmm;
 hypercholesterolemia, LDL-cholesterol above the target value based on cardiovascular
risk: in the case of no cardiovascular symptoms and high cardiovascular risk LDL-Ch
≥3.0 mmol/L; in the case of high cardiovascular risk (diabetes mellitus, metabolic
syndrome, coronary and peripheral arterial disease) LDL-Ch ≥2.5 mmol/L; in the very
high risk group LDL-Ch ≥ 1.8 mmol/L (ref.)
 reading of the patient information leaflet and signing of an advance declaration of
consent.
The exclusion criteria included the following:
 Contraindications as listed in the summary of product characteristics for lisinoprilamlodipine (10 mg/5 mg, 20 mg/5 mg, 20 mg/10 mg) and rosuvastatin (10 and 20 mg)
products,
 known allergy or oversensitivity to ACE-inhibitors, Ca-channel-blockers or statin
 severe renal disease, malignant disease, unreliable contraception, pregnancy,
breastfeeding.
Trial design, end points
The trial is a prospective observational noninterventional trial. Every inducted patient
received 6 months of follow-up monitoring (a total of 4 visits: initial assessment, month 1,
month 3, month 6). The trial end points were the following:
 Systolic and diastolic blood pressure
 Se-LDL-cholesterol
 ABPM testing parameters (subgroup analysis)
 Clinician's Global Impression of Change (CGIC)
 Adverse reactions that can be presumed to be related to the lisinoprilamlodipine/rosuvastatin therapy (side effects)
 Other safety parameters
The investigational products
lisinopril-amlodipine (10 mg/5 mg, 20 mg/5 mg, 20 mg/10 mg) tablet
rosuvastatin (10 mg, 20 mg) tablet
Trial parameters
Pulse and blood pressure measurement: took place in compliance with the professional
guidelines, after 5 minutes rest, on both arms, two successive times, in a seated position. A
minimum of 2 minutes had to pass between two measurements. For blood pressure
measurement the use of an electronic instrument with an upper-arm cuff was permitted.
Laboratory tests: the laboratory tests performed in compliance with the professional
protocols took place in accordance with the following:

Visit 1 (Patient Induction): blood sugar, se-carbamide, se-creatinin, GFR, SGOT
(ASAT), SGPT (ALAT), CK, t-cholesterol, LDL-cholesterol, HDL-cholesterol,
triglyceride, se-Na, se-K, CRP, uric acid, microalbuminuria

Visits 2-4 (months 1, 3, 6): we performed the repeated laboratory tests, for the purpose
of checking the effectiveness and safety of the antihypertensive and lipid-reducing
therapy, after at least 10 hours of fasting.
Body Mass Index: Following determination of the anthropological data (body weight,
height), a BMI calculation was performed.
ABPM test: Performance of this test was not a compulsory element of the trial; the
data of a total of 9 patients was recorded.
(Clinician's Global Impression of Change (CGIC): During visits 2-4 the treating
physician compared the patient’s current condition with that observed at the beginning of the
trial, and rated (on a scale of 0-7) the extent in which the clinical impression had changed.
Medication administered during the observation
At all the post-induction visits there was an opportunity for dose correction for
efficacy or tolerability reasons in accordance with the professional protocols and summaries
of product characteristics of the investigational products. If the patient’s blood pressure or
LDL-cholesterol failed to reach the target value despite taking the maximum administrable
dose, then the complementary therapy was determined by the treating physician, observing
the guidelines of the Hungarian Society of Hypertension and other professional protocols.
After the final visit the patient received continuous medication therapy in accordance with the
professional protocols.
Registration of the data
The patients’ data was recorded on a trial data form on the basis of the protocol. The
data forms were designed in compliance with the data protection and data handling
requirements, and the form of identification ensured the protection of personal rights.
Statistical evaluation
The analysis of the collected data was processed in accordance with the EU-GCP/ICH
standards. In addition to the customary standard analyses (average, SD, median, T-test), the
statistical analysis of all the clinical and laboratory data was performed with correlation
calculation and variance analysis. We described the change with a 95% confidence interval
between the initial and final visit. In the course of using the statistical procedures we treated a
p<0.05 probability level as significant.
Results
A total of 2,452 patients were inducted into the trial, and at the end of the trial a total
of 2,241 patients’ data were processed; in 211 cases the patients were excluded due to noncompliance with the protocol (predominantly incomplete documentation).
The demographic data of the patients are shown in Table 1 (in progress). The patients’
average age was 63.2 ± 11.4, and their average BMI was 29.1 ± 4.1 kg/m 2. Based on the risk
estimate proposed by the 5th Therapeutic Consensus Conference 6.8% of the patients (158
patients) were in the very high cardiovascular risk group. 48% of the patients suffered from
mild (grade 1) hypertension, and 52% from moderate (grade 2) hypertension. 32% of the
patients had not previously received antihypertensive treatment, while 68% had received the
medication therapies listed in Table 1: 65% monotherapy, 35% combination therapy.
Effect of lisinopril-amlodipine therapy on blood pressure
The change in systolic and diastolic blood pressure precipitated by the lisinoprilamlodipine therapy is shown in Figure 1. Relative to the initial visit, by the 2nd visit both the
systolic and the diastolic blood pressure value had decreased significantly. The extent of the
decrease was further magnified by the time of 4th visit (month 6) as a result of the titration of
the lisinopril-amlodipine dose.
In terms of the heart rate, a decrease that was small in the clinical sense but nevertheless
significant was demonstrable over the 6 months of therapy, in comparison to the starting
value (75.3 ± 8.0/minute vs. 73.3 ± 5.9/minute, p<0.05). If we examined the patients on the
basis of whether they had previously received antihypertensive drug therapy, the efficacy of
lisinopril-amlodipine therapy proved to be independent in this respect: the patients that had
previously received antihypertensive drug therapy reacted similarly to the treatment-naive
patients in terms of the extent of the systolic and diastolic blood pressure reduction. In the
subgroup analyses, we detected no significant differences, in terms of the starting systolic
blood pressure and heart rate, between the groups with diabetes mellitus, metabolic syndrome
and peripheral arterial disease, and the group that was free of these related conditions (Table
3). Minimal, but nevertheless statistically significant, differences were detectable in their
initial diastolic blood pressure readings (p<0.05). The change in systolic and diastolic blood
pressure precipitated by the Lisinopril-amlodipine therapy was the same in the examined
subgroups (Table 3).
Applied dose of lisinopril-amlodipine
The distribution of the dose of lisinopril-amlodipine applied in our trial (10 mg/5 mg,
20 mg/5 mg, 20 mg/10 mg) is shown in Figure 2.
Efficacy of lisinopril-amlodipine therapy
We regarded the lisinopril-amlodipine therapy as efficacious if blood pressure was
below the target value for the risk group. The <140/90 Hgmm target value was attained by
68% of the patients by the 2nd visit, and had risen to 91% by the 4th visit as a result of the
dose titration (Figure 3). The <130/80 Hgmm target value was attained by 30% of the patients
by the time of the 2nd visit, and had changed to 57% by the 4th visit. It is important to
emphasise, however, that the 2013 ESC/ESH hypertension protocol published during the trial
abolished the <130/80 Hgmm target blood pressure. In the case of hypertensives over 79 years
of age the target blood pressure was <150/90 Hgmm, and 94% of patients in this subgroup
(n=176) attained the target value in the course of the 6-month therapy.
Effect of rosuvastatin therapy on lipid levels
The change in total cholesterol and LDL-cholesterol precipitated by the rosuvastatin
therapy is shown in Figure 4. Relative to the starting value, by the 2nd visit the total
cholesterol and se-LDL-cholesterol levels had decreased significantly, and the extent of this
reduction was further magnified by the time of the 4th visit (month 6) as a consequence of the
dose titration. Serum triglyceride also showed a significant decrease, and HDL-cholesterol a
significant increase, during the observation period (p<0.05, Table 2).
Applied dose of rosuvastatin
The distribution of the dose of rosuvastatin applied in our trial (10 mg, 20 mg) is
shown in Figure 5.
Efficacy of rosuvastatin therapy
We regarded the rosuvastatin therapy as efficacious if the se-LDL-cholesterol level
was below the target value for the risk group. The <3.0 mmol/l target value was attained by
59% of the patients by the time of the 3rd visit, and this had risen to 67% by the 4th visit due
to the dose titration (Figure 6). In response to the 6-month rosuvastatin therapy the proportion
of patients attaining the <2.5 mmol/l target value was 49%, while the <1.8 mmol/l target
value was attained by 40% of the patients.
Effect of the therapy on the Clinician's Global Impression of Change (CGIC)
The results of the CGIC questionnaire showed significant (63.2%), moderate (20.8%)
and limited (8.7%) improvements in response to lisinopril-amlodipine/rosuvastatin therapy,
with a low proportion of unchanged condition (6.7%) and a minimal extent of deterioration
(0.58%).
Change in laboratory parameters during the therapy
The 6-month lisinopril-amlodipine/rosuvastatin therapy resulted in a significant,
clinically material decrease in total cholesterol, LDL-cholesterol, triglyceride, uric acid,
microalbumin, CRP and blood sugar values; a clinically minimal decrease was shown in the
potassium values (p<0.05), while in respect of the GPT, CN, creatinin and sodium we
observed no significant change (Table 2, enclosed separately). An increase that was minimal
in clinical terms but nevertheless statistically significant was demonstrable in the GOT, CK
and HDL-cholesterol levels.
Adverse events
During the 6 months of the trial we observed adverse events that can be linked to the
therapy in 4.5% (98 patients) of the 2,241 patients inducted into the trial. Most of the total of
148 adverse events were of mild intensity, and in 4 cases they were of moderate intensity. The
events did not necessitate hospital treatment. The majority of the adverse events comprised
dry cough (3.1%), swollen feet and legs (2.2%), muscle pain (1.1%), dizziness (0.2%). The
lisinopril-amlodipine therapy was suspended in a total of 9 cases, and the rosuvastatin therapy
in 10 cases. The reasons for this were a failure to attend the control visit in 2 cases, dry cough
(5 cases), swollen feet and legs 2) and muscle pain (8).
Summary
The most important way of reducing atherosclerotic events is by influencing the
cardiovascular risk factors. The most important factors in this regard are: smoking, high blood
pressure and hyperlipidemia. The new European and American protocols (ESC, ACC/AHA,
JNC8, ASH) have considerably modified the cardiovascular risk rating, and the definition of
the target value considered to be necessary in anti-lipid therapy. It is important to emphasis,
however, that as the main guideline for anti-lipid treatment the protocols continued to
highlight statin-based therapies. Any statin is capable of reducing the LDL-cholesterol level;
however, the anti-lipid effect has proven to be different for the various statins. In the
STELLAR trial the LDL-cholesterol reduction, among the investigated statins (pravastatin,
simvastatin, atorvastatin, rosuvastatin), rosuvastatin proved to be the most efficacious. At a 40
mg daily dose a 55% decrease was demonstrable.
The newly published European hypertension protocol did not highlight any of the 5
main drug classes (BB, ACE-inhibitor, ARB, CaA, diuretic) in monotherapy, but it did
mention that the use of combination products should be given preference with a view to
improving cooperation on the part of patients, especially in the light of the typically low
therapy-loyalty of hypertension patients. Among the drug combinations, it is recommended to
combine one of the inhibitors of the renin-angiotensin-aldosterone system (ACE-inhibitor or
ARB) with a diuretic or CaA. The combination of ACE-inhibitor and long-acting CaA
facilitates effective blood pressure control, but is also shown to result in target organ
protection and produce a decrease in cardiovascular events that is independent from, and
exceeds, the extent of the reduction in blood pressure (ref.).
In our clinical trial we analysed the effectiveness and safety of lisinopril/amlodipine
fixed-dose combination antihypertensive drug therapy and cholesterol-reducing rosuvastatin
free-drug combination therapy in patients suffering from concomitant hypertension and
hypercholesterolism with a high and very high cardiovascular risk. The importance of our
trial, besides the high case number, lies in the fact that we conducted it in respect of high-risk
patient groups, in the presence of related conditions, where several risk factors were known to
exist simultaneously. Managing the risk factors, which for patients means continuously taking
several medicines, often causes problems and detracts from compliance with the drug regime.
The wide range of doses of the lisinopril-amlodipine fixed-dose combination (10mg/5mg,
20mg/5mg, 20mg/10mg) allows for personalised treatment and attainment of the target blood
pressure without the need for the patient to take more pills. This considerably improves
cooperation, the continuous taking of the medication, and ultimately cardiovascular morbidity
and mortality.
Our results showed lisinopril/amlodipine-based therapy to be effective for the majority
of the patients. In the case of symptom-free high cardiovascular risk hypertensive patients, the
previous above-target (140/90 Hgmm) blood pressure reading fell below the target value
during 3 months of therapy in 68% of cases, and thus proportion had increased to 91% by the
end of the 6-month course of therapy. In the presence of related conditions 57% of the
patients had attained the 130/80 Hgmm target value by the end of the trial. It is important,
however, to emphasise that the 2013 ESC/ESH hypertension protocol that was published
during the trial cancelled the <130/80 Hgmm target blood pressure reading (11). In our trial,
at induction the patients’ blood pressure was not at the target value in spite of the high and
very high cardiovascular risk. In this patient group, from a clinical perspective the importance
of attaining the target value is compounded. Based on the presented results, fixed-dose
combination lisinopril/amlodipine-based therapy is also effective in reducing blood pressurereducing in patients who had previously received treatment but did not attain the target value.
If we examined the patients on the basis of whether they had previously received
antihypertensive drug therapy, the efficacy of lisinopril-amlodipine therapy proved to be
independent in this respect: the patients that had previously received antihypertensive drug
therapy reacted similarly to the treatment-naive patients in terms of the extent of the systolic
and diastolic blood pressure reduction. In the course of the subgroup analyses, in the groups
with diabetes mellitus, metabolic syndrome and peripheral arterial disease, we detected no
significant difference in the efficacy of lisinopril-amlodipine-based antihypertensive therapy.
In our trial, the sustained, continuous use of rosuvastatin significantly reduced the
LDL-cholesterol level: with 6 months of therapy, 67% of the patients attained the target value
of below 3.0 mmol/l. The proportion of patients attaining the <2.5 mmol/l target value was
49%, while the <1.8 mmol/l target value was reached by 40% of the patients. The reduction in
total cholesterol and triglyceride (25% and 23% respectively), and the increase in HDLcholesterol (6%) was also significant. It should be emphasised that the substantial
improvements observed in the lipid profile occurred in the patient population with a high
cardiovascular risk, where 48% of the patients had previously received statin therapy but
despite this their LDL-cholesterol level was not at the target value. In our trial, in the case of
type-2 diabetes mellitus and metabolic syndrome significant positive changes were
demonstrable, corresponding to the earlier ones, in respect of the lipid components;
meanwhile we found no appreciable difference between the lipid value changes of the two
groups.
Based
on
the
laboratory
tests,
with
the
6-month
course
of
lisinopril-
amlodipine/rosuvastatin therapy we detected a significant decrease in the CRP value. Our trial
outcome correlates well with the results of the JUPITER trial, although the extent of the
decrease falls short of the one detected in that study. This is probably due to the differing
profile of the patients involved in the trial: the JUPITER trial’s considerable CRP reduction
and pleiotropic effect was achieved against the backdrop of a normal LDL-cholesterol level
and elevated CRP. Especially worthy of note in our trial is the statistically significant and
clinically important decrease in the laboratory parameters that are known to be independent
risk factors: uric acid, microalbumin and blood sugar. Our results correlate well with the
observations of the ASCOT BPLA study: When using an ACE-inhibitor - Ca-channel-blocker
combination, in addition to the cerebrovascular and cardiovascular risk reduction, the
incidence of new type-2 diabetes also proved to be lower in comparison to the beta-blocker diuretic combination (11).
An increase that was minimal in clinical terms but nevertheless statistically significant
was demonstrable in terms of the GOT and CK levels. According to our results, a CK increase
of more than 200 IE occurred in 0.92% of cases, and GOT values of over 60 IE in 0.9%. It
should be noted, however, that in the JUPITER trial no difference was detected in these two
parameters in comparison to the placebo group. Further studies also highlighted that an
increase in the CK level occurs is rarest with the use of rosuvastatin (ref).
The tolerability of the therapy is excellent or can be rated as good for the vast majority
of patients; the patients’ quality of life increased significantly, and we observed a minimal
overall deterioration in the condition of only 0.58% of the patients. No serious adverse effects
occurred during the trial. The majority of the adverse events took the form of dry cough
(3.1%), swollen feet and legs (2.2%) and muscle pain (1.1%). The lisinoprilamlodipine/rosuvastatin therapy was suspended in a total of 19 cases. This was mainly
attributed to dry cough and muscle pain.
Based on the results of our clinical trial and the literature data detailed above, it can be
concluded that lisinopril/amlodipine fixed-dose combination antihypertensive drug therapy
and rosuvastatin free-drug combination therapy may be used effectively and safely in patients
suffering from concomitant mild or moderate hypertension and hypercholesterolemia with a
high and very high cardiovascular risk.
References
1. WHO Library Cataloguing-in-Publication Data, World health statistics. ISBN 978 92 4
156359, 2008.
2. Yusuf S Two decades of progress in preventing vascular disease. The Lancet 2002; 360:2-3
3. Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of more
intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in
26 randomised trials. Lancet 2010;376:1670–1681.
4. Robinson JG, Wang S, Smith BJ, Jacobson TA. Meta-analysis of the relationship between
non-high-density lipoprotein cholesterol reduction and coronary heart disease risk. J Am Coll
Cardiol 2009;53:316–322.
5. Swedberg K, Komajda M, Böhm M et al for the SHIFT Investigators. Ivabradine and
outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet
2010; 376: 875–85.
6. The ACCOMPLISH Investigators; Avoiding Cardiovascular Events Through Combination
Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) Trial. N Engl J Med
2008; 359:2417-28.
7. Mancia G, De Backer G, Dominiczak A, et al 2007 Guidelines for the management of
arterial hypertension: The Task Force for the Management of Arterial Hypertension of the
European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC).
Eur Heart J. 2007;28: 1462–536.
8. Kiss I. A hypertoniabetegség felnõttkori és gyermekkori kezelésének szakmai és szervezeti
irányelvei [Professional and organisational guidelines for the adult and paediatric treatment of
hypertension disease]. Position statement and protocol of the Hungarian Society of
Hypertension. Hypertonia és Nephrologia [Hypertension and Nephrology] 2008; 12(S2):85156.
9. Tedesco MA. et al. Effects of monotherapy and combination therapy on blood pressure
control and target organ damage: a randomized prospective intervention study in a large
population of hypertensive patients. J Clin Hypertens 2006; 8: 634–641.
10. Okin RM et al. Regression of electrocardiographic left ventricular hypertrophy during
antihypertensive treatment and the prediction of major cardiovascular events. JAMA 2004;
292:2324–2349.
11. Dahlöf P, et al for the ASCOT Investigators: Prevention of cardiovascular events with an
antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding
bendroflumethiazide as required, in the Anglo- Scandinavia Cardiac Outcomes Trial – Blood
Pressure Lowering Arm (ASCOT–BPLA): a multicentre randomised controlled trial. Lancet
2005; 366:895-9067.
12. Farsang Cs et al for the HAMLET investigators. A Hypertoniában adott AMlodipin 5 mg
és Lisinopril 10 mg tabletták hatékonyságának és tolerálhatóságának összehasonlító
vizsgálata külön és Együtt alkalmazott Terápiaként (HAMLET) – Multicentrikus vizsgálat
eredményei [Comparative study of the effectiveness and tolerability of Amlodipine 5 mg and
Lisinopril 10 mg tablet administered for hypertension as a separate and combined therapy
(HAMLET) – multicenter trial results]. Hypertonia és Nephrologia [Hypertension and
Nephrology] 2004;8:72-78.
13. Farsang Cs, Ábrahám Gy, Kovács P, Karányi Zs, Ofner P Az Amlodipint és Lisinoprilt
tartalmazó Fix gyógyszerkombináció (Lisinopril-amlodipin®) hatásosságának és
biztonságosságának vizsgálata ESSentialis hypertoniás betegeken (ALFESS) [The effectivity
and safety of Amlodipin-Lisinopril fix-combination in patients with essential hypertension
(ALFESS)]. Hypertonia és Nephrologia [Hypertension and Nephrology] 2009; 13 (3):81-87.
14. Scandinavian Simvastatin Survival Study Group: Randomised trial of cholesterol
lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival
Study (4S). Lancet, 1994, 344, 1383–1389.
15. Lipid Study Group: Prevention of cardiovascular events and death with pravastatin in
patients with coronary heart disease and a broad range of initial cholesterol levels: the Long
Trem Intervention with Pravastatin in Ischemic Disease (LIPID) study group. N. Engl. J.
Med., 1998, 339, 1349–1357.
16. Downs, J. R., Clearfi eld, M., Weis, S. et al: Primary prevention of acute coronary events
with lovastatin in men and women with average cholesterol levels: results of
AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA,
1998, 279, 1615–1622.
17. Baigent, C., Keech, A., Kearney, P. M. et al: Cholesterol Treatment Trialist (CTT)
Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective metaanalysis of data from 90,056 participants in 14 randomised trials of statins. Lancet, 2005, 366,
1267–1278.
18. Nissen, S. E., Tuzcu, E. M., Schoenhagen, P. et al: REVERSAL Investigators. Effect of
intensive compared with moderate lipidlowering therapy on progression of coronary
atherosclerosis. A randomized controlled trial. JAMA, 2004, 291, 1071–1080.
19. Nissen, S. E., Nicholls, S. J., Sipahi, I. et al: ASTEROID Investigators. Effect of very
high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial.
JAMA, 2006, 295, 1556–1565.
20. ESC/EAS Guidelines for the management of dyslipidaemias The Task Force for the
management of dyslipidaemias of the European Society of Cardiology (ESC) and the
European Atherosclerosis Society (EAS). European Heart Journal 2011, 32, 1769–1818.
21. Reiber I, Paragh Gy, Márk L et al. Egyre célratörőbb lipid terápiás szokásaink – a magyar
MULTI GAP 2010 eredményei [Becoming more “goal-oriented” in therapy of dyslipidemias
– results of the Hungarian MULTI GAP 2010 study]. Orvosi Hetilap [Medical Weekly] 2011,
152: 822-827.
22. Jones, P. H., Davidson, M. H., Stein, E. A. et al: STELLAR Study Goup. Comparison of
the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across
doses. Am. J. Cardiol., 2003, 92, 152–160.
23. Schuster, H., Barter, P. J., Stender, S. et al: Effects of switching statins on achievement of
lipid goals: Measuring Effective Reductions in Cholesterol Using Rosuvastatin Therapy
(MERCURY I) study. Am. Heart. J., 2004, 147, 705–712.
24. Course, J. R., Raichlen, J. S., Riley, W. A. et al: METEOR Study Group. Effect of
rosuvastatin on progression of carotid intima-media thickness in low risk individuals with
subclinical atherosclerosis. JAMA, 2007, 297, 1344–1353.
25. Lablanche, J. M., Leone, A., Merkely, B. et al: Comparison of the effi cacy of rosuvastatin
versus atorvastatin in reducing apolipoprotein B/apolipoprotein A-1 ration in patients with
acute coronary syndrome: Results of the CENTAURUS study. Archives Cardiovascular
Diseases, 2010, 103, 160–169.
26. Ridker, P. M., Danielson, E., Fonseca, F. A. H. et al: Reduction in C-reactive protein and
LDL-cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective
study of the JUPITER trial. Lancet, 2009, 373, 1175–1182.
27. Emerging Risk Factors Collaboration: C-reactive protein concentration and risk of
coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet,
2010, 375, 132–140.
28. Guidelines for Good Pharmacoepidemiology Practices (GPP), Revision 2: April 2007 ,
International
Society
of
pharmacoepidemilogy,
http://www.pharmacoepi.org/resources/guidelines_08027.cfm#1