Vol.48 - Número 2, Abril/Junio 2019 Imprimir sólo la columna central

Achievement of low density lipoprotein cholesterol targets in 18 countries outside Western Europe: International Cholesterol Management Practice Study (ICLPS).
Argentine subanalysis.


Estudio patrocinado por Sanofi-Aventis.
1. Prevención Cardiovascular Salta, Salta; 2. Hospital Austral, Buenos Aires; 3. Instituto Cardiovascular Lezica, Buenos Aires; 4. Hospital Italiano de Buenos Aires, Buenos Aires;
5. CardioAlem Investigaciones, Buenos Aires; 6. Consultorio Privado, Mar del Plata, Buenos Aires; 7. Fundación Favaloro, Buenos Aires; 8. Instituto Médico DAMIC / Fundación Rusculleda, Córdoba; 9. Instituto Cardiología de Corrientes, Corrientes; 10. Hospital Austral, FLENI, Buenos Aires.
(4400) Salta, Argentina.



Little is known about the achievement of low-density lipoprotein cholesterol targets in patients in cardiovascular risk receiving stable lipid-lowering therapy in countries outside Western Europe.
Methods: This cross-sectional observational study was conducted since August 2015 to August 2016 in 18 countries outside Western Europe, including Argentina. Patients (n = 9049) treated for >3 months with lipid lowering therapy and in whom an LDL-C measurement was available within the previous 12 months were included. In this paper we report results from Argentine patients.
Results: Argentina enrolled 307 patients. The mean +SD age was 63.7 +12.1 years, 59.6% of patients were men and the mean +SD LDL-C value on therapy was 96.3 +36.7 mg/dl. At enrolment, 97.4% of patients were receiving a statin (23.1% on high-intensity treatment), and 14.7 % were receiving the highest dose available. The SCORE scale was used to measure cardiovascular risk. In Very High Risk patients, the level of risk was diagnosed in only 39.1% of patients. The target for Very High Risk (LDL-C <70 mg/dl) was achieved in 27.8% of patients in this group; the target for High Risk (LDL-C <100 mg/dl) was achieved in 55.9 % of patients in this group. Statin intolerance was reported in <10% of patients.
Conclusions: This study shows a low percentage of patients reaching the goals, together with a low percentage of use of high-intensity statins. The low use of high-intensity statins is not justified by the low percentage (<10%) of patients with some intolerance to statins. The percentage of accuracy in the diagnosis of risk in these patients is also low.
Both the inaccuracy to detect the Very High or the High Risk, and the low success rate to reach objectives can be corrected, at least in part, with continuous education for physicians and patients.
Key words: LDL-C targets. Cardiovascular Risk. Statins.


The relationship between low-density lipoprotein cholesterol (LDL-C) and cardiovascular risk is clearly established. For every 40 mg/dl of LDL-C decrease, said risk decreases by 22% [1].

Statins are first-choice drugs to decrease LDL-C values. Since 2011, the ESC/EAS (European Society of Cardiology/European Atherosclerosis Society) guidelines suggest for patients with a high cardiovascular risk a target value of LDL-C <100 mg/dl, and in those in very high risk, a target <70 mg/dl, or ≥50% if said goal cannot be reached. Recent American guidelines from 2018 propose similar targets [2,3].

Studies made in the past, in the northern hemisphere, revealed that the proportion of patients reaching the proposed goals according to one guideline or another is far from optimal, 3 to 5 every 10 patients do not reach the targets [4-7]. Different reasons explain it: from the presence of familial hypercholesterolemia with low response to lipid-lowering agents, to intolerance to medication, including the patient not adhering to the treatment, indications of physicians not adjusted to guidelines (called Therapeutic Inertia), use of other drugs that are not as efficient, etc. All of them are obstacles to obtain a proper control of LDL-C values in a population with cardiovascular risk.

The ICLPS study, that was observational, cross-sectional, international and open, was designed to evaluate in different countries outside the US and western Europe, the pattern of use of lipid-lowering treatment and its variations according to the environment, and the basal characteristics of patients and physicians. The study attempts to reflect what occurs in real life, in a wide basal cardiovascular risk range of patients, and considering physicians from different specialties involved in the management of this type of patients [8].

The data presented in this paper corresponds only to the results from Argentina.

Primary goal:
To evaluate the percentage of cardiovascular patients in Very High Risk (VHR) and High Risk (HR) reaching the target value for LDL-C according to the ESC/EAS guidelines from 2011.

Secondary goals:
To evaluate the percentage of patients reaching LDL-C targets, according to definitions by the ESC/EAS guidelines.
To compare the state of cardiovascular risk estimated according to the SCORE scale with risk evaluation made by the investigators.

To evaluate the percentage of patients declared “intolerant to statins” according to different definitions (intolerant to 1, 2 or ≥3 statins) and the most frequently reported intolerance symptoms.

To compare the proportion of patients diagnosed with familial hypercholesterolemia versus its diagnosis according to Dutch criteria [2].


International, multicenter, observational, cross-sectional study that included 9049 patients [8]. The Argentine portion corresponded to 307 patients added by 10 investigators. To prevent a selection bias, the investigators were chosen randomly and it was established that patients should be included consecutively for two weeks. Data collection was made in a single visit. The study had no follow-up.

Inclusion criteria: Age ≥18 years, having received stable lipid-lowering treatment for at least 3 months, and having an LDL-C value determined after 3 months of stable treatment. Patients had to sign an informed consent. The study was approved by a Committee on Clinical Investigation Ethics.

Exclusion criteria: Being a participant in a clinical trial and having received a PCSK9 inhibitor within the last 6 months before being included in the study.

There were numerous variables considered, among them the following are highlighted in this list:

  • Age and gender.
  • Presence of tendinous xanthoma and corneal arcus.
  • Cardiovascular risk factors: smoking, hypertension, diabetes, physical activity, obesity and presence of metabolic syndrome.
  • History of dyslipidemia: diagnosis of dyslipidemia/hypercholesterolemia, lipid profile, estimated etiology of hypercholesterolemia.
  • Cardiovascular history: CAD, cerebrovascular or peripheral artery disease, chronic kidney disease, heart failure.
  • Lipids: estimated or measured LDL-C and if available: total cholesterol, HDL cholesterol and triglycerides.
  • Lipid-lowering treatments: statins, fibrates, bile acid sequestrants, omega-3 fatty acids, etc.
  • Personal evaluation by the investigator on: cardiovascular risk level for the patients and LDL cholesterol target value.

Ethical considerations: This study meets the international ethical guidelines on clinical investigation, and was approved by Committees on Investigation Ethics from each Institution. All participants signed a written informed consent.


a) about physicians:
Ten Argentine physicians participated: Average age 57.5 years and average 33 years of professional practice. All manifested following clinical practice guidelines and working in urban areas. Nine developed their activities in private institutions.

They defined intolerance to statins as intolerance to 3 or more drugs in 6 cases; 3 accepted intolerance when 2 different drugs were not tolerated, and only one considered it as intolerance to one statin.

b) about patients:
The basal characteristics of patients are shown in Table 1.

Table 1. Basal characteristics of patients. N=307
    N %
  Mean age +SD (years) 63.7 + 12.1
  Documented previous pathology
• CAD*
• Cerebrovascular disease*
• Peripheral vascular disease*
• Chronic kidney disease
• Heart failure
• Chronic obstructive pulmonary disease
• Cancer
  Cardiovascular risk according to the SCORE scale
• Very high risk (VHR)
• High risk (HR)
• Moderate risk (MR)
• Undefined risk (UR)
*All of these cases occurred in VHR patients


c) about dyslipidemia:
In 298 patients (97.1%), the diagnosis of dyslipidemia had been made. The etiology of hypercholesterolemia was interpreted as secondary in 54.9% of cases, primary or familial in 21.2% and etiology could not be defined in 23.9%. In more than 90% of cases of primary hypercholesterolemia, no genetic test had been done. Eight patients presented tendinous xanthoma (7 of them of HR or VHR) and 30 corneal arcus (28 of HR or VHR).

d) cardiovascular risk factors:
Besides 97.1% of patients with previous diagnosis of dyslipidemia, 72.6% of hypertensive patients stand out. The percentages of risk factors presented in this sample are observed in Table 2.

Table 2 . Risk factors at the time of enrollment to the study
  Factor %
Diabetes Mellitus
Former smokers
Obesity (BMI >30 kg/m2)
Metabolic syndrome (ATPIII) #
Metabolic syndrome (IDF) ##
# As defined by the Atherosclerosis Treatment Panel III
**As defined by the International Diabetes Federation


e) lipid values:
These data are shown in Table 3. As the only inclusion criteria in terms of lipids was LDL-C under present treatment, the data on other lipid values, previous or under present treatment, were not available in all 307 patients.
e.1. achievement of lipid targets:
The target of LDL-C <100 mg/dl was achieved by 55.9% of HR patients, and 27.8% of VHR patients achieved the target <70 mg/dl.

Table 3. Lipid values before and during lipid-lowering treatment in mg/dl + SD.
  Lipids Before (n/n total) In the Study (n/n total)
  LDL cholesterol
Total cholesterol
HDL cholesterol
167.1 + 40.1
247.8 + 40.8
48.9 + 14.3
168.4 + 94.6
96.3 + 36.7
169.5 + 40.7
49.7 + 18.6
134.3 + 66.2


In 177 patients in whom LDL-C values were available before treatment, the mean percentage of LDL-C decrease was 41.5%.
A value of Glomerular Filtration Rate was obtained in 226 patients. The median was 78.8 ml/min/1.73 m2, and only 9 (2.9%) presented GFR <45 ml/min/1.73 m2.

f) lipid-lowering treatment:
Statins: They were used in 299 patients (97.4%, 98.7% in VHR patients, p=NS). In 240 of them (78.2%), they were used in isolation, in 34 (11.4%) they were combined with cholesterol absorption inhibitors, in 15 (5%) they were combined with fibrates, and in the remaining 10 patients, they were used in other combinations of 2 or 3 drugs.

Cholesterol absorption inhibitors: 40 patients (13%).

Fibrates: 22 patients (7.2%). In 3 cases, in isolation (<1%).

Considering all drugs in isolation or in combination, the most used ones were: statins in isolation in 78.2%, statins in combination with cholesterol absorption inhibitors in 11.1%, statins combined with fibrates in 4.9% and the rest of the options in each case between 0.3% and 1%. There were no differences between the use of statins in isolation or in combination between the different groups.

From the 299 patients treated with statins, only 69 (23.1%) were receiving high-intensity treatment (atorvastatin 40-80 mg/day or rosuvastatin 20-40 mg/day), and only 44 (14.7%) the highest dose sold in this country. Using high-intensity statin therapy ranged from 8.3% in MR (Moderate Risk) and 28.9% in VHR (p=0.01). There were no differences in the use of the highest dose between groups.

The reasons put forward not to prescribe the highest dose were: satisfaction with a low LDL-C level under the current regimen in 74.5% (187 patients) and intolerance to higher doses in 16.7% (42 patients), by muscular symptoms (26 cases, only in 1 in association with CPK elevation more than 4 times the maximum normal value) and gastrointestinal symptoms (12 cases). In a lower proportion, the cost was given as a reason (8.4%), as well as the presence of co-morbidities (6.4%). There was no difference between groups in regard to the reasons not to use the highest dose.

In 23.5% of cases, another statin had been prescribed before the one used currently (in more than 60% of them only one); the most frequent reasons for change were non-satisfaction with LDL-C levels with the previous regimen (42.9%) and intolerance (38.6%), linked to muscular symptoms in 4 every 5 cases (and mainly gastrointestinal in the rest). There was no difference between groups.

g) concomitant lipid-lowering treatment:
Fifty percent of patients were treated with aspirin, alone or in combination with other antiplatelet agents; 68.5% with angiotensin-converting-enzyme inhibitors or angiotensin II receptor blockers, 18.2% with diuretics and 44.3% with beta blockers. 23.5% with lipid-lowering agents, and 5% with insulin. Using other chronic medications was very rare.

i) definition of risk by the investigator:
Between MR patients, physicians interpreted MR in 34.5%. They assessed HR in 33.9% and VHR in 34.5%. The remaining 10.4% was estimated to be in low risk.

Between HR patients, physicians interpreted HR in 37.7%. They assessed VHR in 5.2%, MR in 46.8%. The remaining 10.4% was estimated to be in low risk.

Between VHR patients, physicians interpreted VHR in 39.1%. They assessed HR in 39.7% and MR in 20.5%. The remaining 0.7% were estimated to be in low risk.

Between patients in Undefined Risk (UR), physicians interpreted MR in 40.5%. They assessed HR in 26.4% and VHR in 2.4%. In the remaining 31%, they assessed low risk.

To conclude, there was a tendency to underestimate risk in most of VHR and HR patients.
The target of LDL-C defined by physicians for patients in all the analyzed groups had median of 100 mg/dl. It is interesting to point out that the range of targets varied for MR patients between 70 and 160 mg/dl; for HR between 70 and 130 mg/dl; for VHR between 60 and 130 mg/dl; and for UR between 70 and 130 mg/dl.

In 177 cases, the diagnosis of familial hypercholesterolemia according to Dutch criteria could be collected: it was definitive in 16 patients (8 in HR and 8 in VHR).



  • Analysis according to LDL-C target reached:

When considering the 265 patients in defined risk, 113 (46%) reached the LDL-C target. There were some differences between those that reached and did not reach the treatment targets, in previous conditions and in lipid values previous to the lipid-lowering treatment, shown in Table 4. There were no differences in the prevalence of diabetes, hypertension or performance of physical activity.

Table 4. Differences between patients that reached and did not reach lipid-lowering therapy targets.
  Item Reached Did not reach P value
  Female gender
Heart failure
Cerebrovascular disease
Chronic kidney disease
Smokers-former smokers
Obesity (BMI > 30 kg/m2)
42.5 %


  Lipid values before the study    
  LDL cholesterol
Total cholesterol
HDL cholesterol
160.7 + 31.2
240.9 + 34.0
49.3 + 13.6
164.9 + 89.2
173.2 + 46.3
254.9 + 45.9
48.5 + 15.3
172.8 + 101.3
Lipid values before the study are expressed in mg/dl + SD.


At the time of entering the study, LDL-C values were obviously lower among those that reached the target, 71±18.8 mg/dl vs those that did not reach it, 113.3±30.4 mg/dl (p<0.0001).

Total cholesterol values were also lower in those that reached the target: 145.5±27.8 mg/dl vs 186.6±35.5 in those that did not reach it (p<0.0001).

There was no significant difference between HDL values, 49.5±14.8 mg/dl vs 48.1±13.8 mg/dl, or in triglycerides, 122.4±55.3 mg/dl and 143.6±71.8 mg/dl (p=NS); nor in glycated hemoglobin or creatinine.

Use of statins: The use of statins was similar in both groups, but there was a tendency in those that reached the LDL-C target, to a lower use of fibrates (4.1% vs 8.4%, p=NS) and to a greater use of cholesterol absorption inhibitors (18.9% vs 9.1%, p=0.02).

The proportions of patients with high-intensity statin therapy and treated with the maximum dose sold in the whole country, were similar in both groups¸ and according to those mentioned globally. The reasons not to use the maximum doses differed between the two groups: in the group that reached the target, almost 95% argued to be satisfied with the LDL level obtained, not requiring to use higher doses; between those who did not reach 57.4% the same reason was expressed, against 27.8% that argued intolerance (59.4% of them due to muscular symptoms and 34.4% due to gastrointestinal symptoms). A similar proportion had received another statin before (according to overall figures) with no differences in terms of causes for change.

Concomitant treatment: The patients that reached the target received less aspirin (47% vs 58%, p=0.07), and antiplatelet agents in general (54% vs 74.5%, p=0.0007). There was no difference in the use of angiotensin-converting-enzyme inhibitors or angiotensin II receptor blockers and diuretics, but there was less use of beta blockers (41.8% vs 52.4%, p=0.053) and greater use of lipid-lowering agents (34.4% vs 21%, p=0.04).


The LDL-C target <70 mg/dl for VHR patients was reached by 27.8% of them, and the target <100 mg/dl between HR patients was reached by 55.9% of them. VHR patients received high-intensity statins therapy in 28.9% of cases.

In regard to the assessment of risk: between VHR patients, this level was estimated in 39.1% and between HR patients, 37.7% of cases.

In relation to intolerance to statins, 23.5% of patients had used another statin before the one stated in the study, intolerance was the cause for change in 38.6% of them, most linked to muscular symptoms, but only 1 patient had serum CPK elevation 4 times the normal value.

This study shows a low percentage of patients that reach targets, but jointly with a low percentage of high-intensity statin therapy use. The low use of high-intensity statin therapy is not justified by the percentage of patients with some intolerance to statins, which is also very low (<10% of the total sample). The percentage of accuracy in the diagnosis of risk in these patients is also low.

Both the inaccuracy to detect VHR or HR, and a low rate of success to reach targets could be corrected, at least in part, with continuous medical education addressing these issues.


The sample was not randomized; to decrease the bias, the selection of investigators was randomized and patients were admitted consecutively over a brief period of 2 weeks.

There were only 307 patients added by just 10 investigators, so the extrapolation of these to the general population should be done with caution, taking this limitation into account.




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Publication: June 2019


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