The evolution of the lipid profiles and CV risk in relation to our patient’s increased treatment.
The European Atherosclerosis Society and the European Society of Cardiology have made new recommendations regarding the treatment of dyslipidaemia (1). Such recommendations build upon the “Joint European Societies' Task Force Guidelines on the Prevention of CVD in Clinical Practice" of 2007 [1, 2]. The most important changes include the redefinition of the risk categories and the addition of a ‘very high-risk’ category. For these new risk categories, the LDL-C targets have been redefined. In the highest risk individuals, the lowering of LDL to 70 mg/dl is recommended. Furthermore, HDL-c has been added to the new SCORE risk chart and non-HDL cholesterol is now considered to be a secondary target.
In this study, we illustrate how these guidelines can be used in clinical practice. We also give some tips on how to make them more user-friendly for clinicians (Figure 1). The discussed case (Clinical Case 1) was developed to combine a series of difficulties in therapeutic decision-making. We accepted the principle that any correctable secondary causes of dyslipidaemia had been excluded and that the patient had already received all the care to improve the other risk factors but without real (enough) success. These risk factors included smoking cessation, weight loss and/or blood pressure reduction. Unfortunately, this case is far from an exception. The reality is that it is often more difficult to quantitatively reduce risk factors, than it is to reduce cholesterol levels.
2. First question: What is the cardiovascular risk of this patient?
To determine whether the patient is in the highest/high-risk category, we propose the acronym "C.A.R.D.I.A.SCORE". This will make it easy to remember (Figure 1).
2.1. Acronym « C.A.R.D.I.A. SCORE »
If there is an history of
For patients who show an isolated, yet severe, risk factor
All other individuals who do not present one of the above characteristics should be examined using SCORE (6).
2.2. SCORE with two novelties
Our case (Clinical Case 2) illustrates how a "moderate" 4% risk can be significantly enhanced in refining the other risk factors such as HDL-C, family history and so on. It is possible to calculate the global risk (fatal and non-fatal) simply by multiplying by three for men, by four for women and by a little less for older people. Taking this into consideration, for our female patient of 59 years, we should multiply by three. Thus, the overall risk is 45%. This is another way of expressing the CVD risk (with a higher number!). It should be used to increase our patient’s awareness of CVD and encourage her to be more motivated to follow the regime and take her medication.
3. Second question, how do we treat this patient?
The LDL-C remains the primary target, as in the previous guidelines. The target LDL-C is determined as a function of the patient’s risk.For each risk category, there is a different LDL GOAL. There is also a simplified chart to calculate the LDL reduction percentage to reach that goal. The evidence to decrease LDL-C to such low levels is supported by previous studies that indicate a possible regression of atherosclerotic plaques (i.e., a "rejuvenation" of the arteries) in this condition.
What if the level of LDL-C is unavailable because it is non-computable by the Friedewald formula (when TG levels are above 4.5 mmol/l)? In this case, we should use another target. The alternative target is not the level of total cholesterol, as proposed in the previous guidelines. Instead, it is the level of non HDL-C that will become, in this case, the primary target (see §4).
3.1. Which Statin, What Dose and How Fast
Statin should always be the first line treatment (even for dyslipidaemia mixed with elevations of cholesterol and triglycerides, as we will demonstrate below (§4)). We should begin by prescribing a statin at a dosage that is the most likely to be effective in obtaining the correct reduction target. The rationale to choose the statin type and dosage is quite mathematical and is based on the baseline level, the LDL-C target and knowledge of the different statins’ power (Figure 3). In terms of power (for a same dosage), these are fluvastatin < pravastatin < simvastatin <pitavastatin< atorvastatin < rosuvastatin . Another rule is that, on average, doubling each of the statin dosage leads to a further decline in the rate of LDL-C of 4% to 6%. Another way to intensify the treatment is to associate the statin with one of the other anti-dyslipidaemia drugs (Figure 3). Among these, ezetimibe has the largest (20% to 25%) additional reduction of LDL-C. When the risk is high and the target is not reached, it is important to adjust the treatment as quickly as possible. The compliance and satisfaction of the patient, as well as the physician, depends on it.
3.2. Before prescribing a statin, we will check
Before the initiation of treatment, it is important to ensure that the CK (creatine phosphokinase) levels are not too high. If they are very high (> 5 times the upper limit of normal), it is better to delay and to check again six weeks later. Furthermore, it is important to determine the cause of these levels (intense physical exercise, trauma or recent intramuscular injection). To reduce the risk of muscle side effects, we have to be more vigilant in elderly patients or in cases where the simultaneous use of treatment is interfering (via cytochrome P 450) with the metabolism of the proposed statin. We also have to be particularly careful if the patient has previously suffered from hepatic or renal insufficiencies.
For our patient in the very high-risk category, the LDL-C target is below 1.8 mmol/l. To achieve this target, we should reduce the patient’s LDL-C by 40% (Clinical Case 3).
4. Third question, how to follow up the patient?
In order to verify the effectiveness and safety of the patient’s prescription, the improved guidelines recommend a patient follow up eight weeks later. Once the lipid levels have reached the target levels (according to the risk of the patient) and a safe level is maintained, an annual follow up will suffice.
4.1. Tolerance monitoring
Throughout the therapy, the monitoring of liver enzymes (Figure 5) is required. In subjects complaining of muscle pain, the muscle enzymes should be analysed. As long as the enzymes are not too high (< 3 x the upper limit of normal or ULN), we should continue the statin. However, if the enzymes exceed by 3 x ULN for liver enzymes or 5 X ULN for muscle enzymes (Figure 5), the statins should be stopped. Furthermore, the enzymes should be checked four to six weeks later (or two weeks later if the CK is very high). For high elevation of the CK, we should check the renal function. When the enzymes return to a normal value, treatment (or an alternative treatment) should be carefully reintroduced. In all cases, other common causes of the elevation of these enzymes should be excluded. In the instance of high CK, this means intensive muscle efforts and injuries (including intramuscular injections, etc.). For cases of high ALT, this means weight gain, excess of sugar, fat or alcohol, steatosis, hepatitis, lithiasis migration and other medications, etc.
4.2. Efficacy monitoring
If the target is not achieved and, especially, if the observed reduction is lower than expected, as is the case here (Clinical Case 4), we should first check whether the patient has been compliant. We know that, after one year, approximately half of patients do not correctly take their medication . If the patient has been compliant with her medication, it is possible that the inadequate response is due to a resistance to the statin. This occurs in 10% of patients. If this is the case, we should adapt the treatment.
4.2.1. Why is it important that the target is reached?
In a recent meta-analysis of the results of 118,000 subjects from 26 intervention trials with statins, there was evidence of a relationship between the reduction of LDL-C and the reduction of the incidence of CV disease in 4-5 years. Every decrease of 1 mmol/l for LDL - C by a statin (Figure 4) was associated with a relative reduction in about 20% coronary events, stroke and heart deaths . This relationship was universal (regardless of age, sex and other risk factors). Furthermore, it was almost linear over the range of studied LDL-C levels.
The absolute benefit produced by statins not only depends on their capacity to lower LDL-C but also, on the initial CV risk. Thus, the greater the initial CV risk, the greater the reduction of absolute risk. In such cases, it is crucial to ensure the reduction of LDL-C. For our patient (Clinical Case 4 and Figure 4), we calculated that a reduction ofLDL-C to 1.6 mmol/l (below the target of 1.8 mmol/l), instead of the current reached level of 2.3 mmol/l (Clinical Case 4), should reduce the risk of mortality from 12% to 10% CV. This should also reduce the CV global risk (multiplied by three) from 36% to 30% (Figure 4). This means that if this target was not achieved in 100 patients, six (30-36%) patients would experience a CV event and two patients would die (10%-12%). This highlights the importance of achieving values below the target, even if it sometimes seems difficult.
4.2.2. What to do if the target is not reached?
In our patient’s case (Clinical Case 5), we should try to obtain her compliance by reassuring her. If, in spite of this, the target is still not reached, we should adapt the treatment. This can be achieved by increasing the dosage of the statin (doubling each = 6% further LDL reduction) or replacing it with a more powerful statin. Another option is to combine the treatment with Ezetimibe (with an additional reduction of 20-25%) (Figure 3). The latter option is particularly useful when the observed reduction appears lower than expected, despite the patient’s compliance with the treatment. Indeed, this suggests that the patient has a resistance to the statins. This usually affects all statins at all doses (the effect of each doubling statin dose does not allow the patient to achieve more than 4% or even 3%).
4.2.3. Reach the target« ASAP2 ».
As mentioned above, the benefit of the LDL-C reduction can be seen within the first year treatment. The goal of "as quickly as possible" is all the more important in patients that are considered as high-risk. In a patient such as ours, there is a 15% risk of her dying from CVD in the next 10 years. Furthermore, there is a 45% (almost a "chance" on 2) risk of her having a global (fatal and non-fatal) CV event in the next 10 years. This means that there is a respective 1.5% risk and 4.5% (almost a "chance" on 20) risk of CV mortality and global CV risk per year. Although this may seem like a relatively small number, the delay in the necessary reduction of LDL-C for a year in 100 individuals (like our patient) would result in at least four to five CV events (including one death). However, in our practice, we should take note of the excuses given by the patient or by ourselves (anniversary cake, Christmas or Easter celebration, carnivals, holidays in all-inclusive hotels, etc., are a few days before blood sampling!). Such legions delay treatment adaption and obtaining satisfactory results. Taking this into consideration, it is clear that a more honest escalation in treatment would be more beneficial for the patient (Figure 6).
5. Fourth question: Should we go beyond LDL?
This leads us to three questions: (1) under statin therapy, does the patient still have a residual CV risk? (2) Is it necessary to target HDL-C and triglycerides? (3) Finally, is there scientific evidence that suggests further intervention would be beneficial? To answer these three questions, the guidelines respond affirmatively. Even after the reduction of LDL–C under the correct value target, a residual risk persists (between 60 and 80% of the initial risk). Part of this residual risk is attributed to the persistence of other alterations in a lipid profile.
Thus, if after the LDL-C correction, the patient still displays a high or very high-risk and has combined dyslipidaemia (triglycerides [TG] high > 1.7 mmol/l and HDL cholesterol [HDL - C] too low < 1.2 mmol/l for men or < 1.4 mmol/l for women), she may benefit from further improvement in her lipid profile.
The next question is: at this stage, how should a therapeutic target be set? Should we correct these levels of HDL-C and triglycerides or should we seek another target? In practice, it is often impossible to completely correct TG and HDL-C levels to achieve levels of 1.7 mmol/l for TG or 1.2 mmol/l in men and1.4 mmol/l in women for HDL-C. On the one hand, TG levels vary too much from one day to the next. On the other hand, HDL-C levels are difficult to increase. For example, a baseline HDL-C at 0.8 mmol/l gives a rise of 20%, equivalent to 0.16 mmol/l. This only allows the HDLL-C levels to reach 1 mmol/l - a difference barely perceptible, given the limited accuracy of laboratory measurements. Thus, the new guidelines recommend a more realistic target: the level of
In fact, as we can understand from the formula of Friedewald, this non-HDL-C is the sum [LDL-C + VLDL cholesterol]. The originality of this parameter is that it integrates all the potentially atherogenic lipoproteins, namely LDL and VLDL. These have a particularly high presence of low HDL-C and high TG (e.g., in the metabolic syndrome) .
The conditions and level of non-HDL-C targets are easy to deduct from the target levels of LDL–C. This is because they integrate the target value of LDL-C (< 1.8 or <2.5 mmol/l) plus the ideal value of VLDL-C (< 0.8 mmol/l; 0.8 is obtained by dividing the ideal 1.7 mmol/l level of TG by 2.2, see the Friedewald formula). Consequently, the level of non-HDL-C should be less than 2.5 mmol/l or 3.3 mmol/l as the risk is very high or high, respectively (Clinical Case 6).
|Time line||0||2 months||6 months||10 months|
< 1,.8 mmol/l
< 70 mg/dl
|Second attempt to correct LDL-C||Non HDL-C < 2.5 mmol/l (↓ LDL-C)||Alternative to ↓ non HDL-C < 2,5 mmol/l (↓ VLDL-C)|
|Current treatment||Baseline||Simva 40 mg||- Better compliance|
- Atorva 40 mg or rosuva 20 mg
|Same as visit 4|
+ ezetimibe 10 mg
|Same as visit 4|
+fenofibrate 145 mg
|Total cholesterol||5,8 mmol/l|
|Non HDL-C||5,8-1,0=4,8 mmol/l|
|LDL reduction (from baseline level)||-0,9 mmol/l (-28%)|
(- 35 mg/dl)
|-1,6 mmol/l (-50%)|
(- 62 mg/dl)
|-2,0 mmol/l (-63%)|
(- 77 mg/dl)
|-1,7 mmol/l (-53%)|
(- 66 mg/dl)
|Relative risk reduction (Absolute risk reduction or ARR)||- 18%|
|> - 34%*|
|SCORE evolution calculated from the initial SCORE and the subsequent ARR||15,0%||12,3%||10,2%||9,0%||<9,9%|
|SCORE evolution estimated from SCORE Chart (see Figure 2).||15,9%||12,2%||10,4%||10,4%||8,1%|
The reduction in the level of non-HDL-C should be achieved by an additional lowering of the LDL-C level. There are a number of ways to do this, including the prescription of a higher statin dosage, a stronger statin, a combination with ezetimibe (if intolerant) or by lowering the level of TG (and therefore, VLDL-C) via the association of the statin with fibrate or niacin (Clinical Case 6).
The new recommendations offer a practical approach. They are more precise in supporting the lipid profile of CV prevention. The four levels of risk and the possible adjustment of the new targets (non-HDL-C or apoB) next to the traditional targets of the LDL–C and HDL-C rate will allow better prescriptions of appropriate therapeutic drugs.
The present case illustrates step by step (visit by visit) the rationale for escalating treatment in order to achieve the best cardiovascular prevention. We hope that such an example can help give a better understanding of the EAS/ESC guidelines. The rigorous mathematical reasoning is, of course, only displayed here to better quantify the benefit of the various therapeutic choices. It is unlikely that it would be used in clinical practice. It is important to note that the practical implementation of guidelines requires the intuitive clinical skill of the practitioner, as well as open discussions with the patient. We would also like to highlight that, if the correction of the lipid profile is accepted as the cornerstone of CV prevention, the importance of lifestyle change (smoking, diet and physical activity) and the need to correct other risk factors should not be forgotten.