Visit-to-Visit LDL Cholesterol and Cardiovascular Outcomes
Visit-to-Visit LDL Cholesterol and Cardiovascular Outcomes
The results of this study indicate that visit-to-visit LDL-C variability is a powerful and independent predictor of any coronary event, any cardiovascular event, death, MI, and stroke, independent of treatment effect and achieved LDL-C levels (Central Illustration). In the adjusted model, each 1-SD increase in LDL-C variability (as measured by ASV) increased the risk of any coronary event by 16%, any cardiovascular event by 11%, death by 23%, MI by 10%, and stroke by 17%, independent of statin dose and achieved LDL-C levels. The association was significant even after controlling for treatment adherence.
(Enlarge Image)
Central Illustration.
Visit-to-Visit LDL-C Variability and Outcomes
Visit-to-visit LDL-C variability was defined as variability in LDL-C values between visits, on the basis of 9,572 patients from the TNT trial. LDL-C variability measured from 3 months onward into random assignment because this was the relatively steady phase in LDL-C after the initial decrease. CV = cardiovascular; LDL-C = low-density lipoprotein cholesterol; MI = myocardial infarction.
Randomized trials, observational studies, andmeta-analyses have shown a significant benefit of statins for primary prevention of cardiovascular events as well as for secondary prevention. The results from these studies indicate that lowering of LDL-C by 1 mmol/l (approximately 39 mg/dl) with a statin reduces the incidence of major vascular events by approximately 20%. The standard statin regimen reduces LDL-C by approximately 30%, with more intensive statin regiment reducing this level by approximately 50%. In addition to a reduction in LDL-C, other pleotropic effects such as anti-inflammatory properties, plaque stabilization, and others appear to contribute to the significant benefit of statin therapy. It is therefore not surprising that statins are the mainstay for prevention and treatment of patients with CAD and are endorsed by major national and international guidelines. Despite this, there remains a residual risk of cardiovascular events even in patients receiving an intensive statin regimen. In the TNT trial, although intensive statin treatment with atorvastatin 80 mg/day reduced cardiovascular events when compared with atorvastatin 10 mg/day, the residual risk of major cardiovascular events was 8.7%, death was 5.7%, MI was 4.9%, and stroke was 2.3%.
Visit-to-visit variability in blood pressure is an independent predictor of adverse cardiovascular events, which suggests that a more uniform/less variable blood pressure is desirable. This is true despite that fact that there is variability in blood pressure measurement with time of day and with stress, activity, and emotions. However, it is not known if the same is applicable to LDL-C control. In the present study, we measured variability in the LDL-C levels from 3 months after the initial decrease onward into random assignment because this was the period in which the LDL-C levels in the 2 treatment arms were relatively stable. The results of the present study indicate a strong and independent effect of visit-to-visit variability measurements on long-term cardiovascular outcomes. Each 1-SD increase in visit-to-visit variability in LDL-C was associated with a significant increase in any coronary event, any cardiovascular event, death, MI, and stroke, and this was independent of treatment effect and achieved LDL-C levels, which suggests that a more uniform and less variable visit-to-visit LDL-C is important. The results of the present study also indicate that visit-tovisit variability in LDL-C was lower with atorvastatin 80 mg/day when compared with atorvastatin 10 mg/day. It therefore lends credence to the American College of Cardiology/American Heart Association blood cholesterol guideline recommendation of moderate- to high-intensity statins in patients with atherothrombotic vascular disease, not only for a more robust reduction in LDL-C but also for less variability in LDL-C. Although the dose of statin was predictive of visit-to-visit LDL-C variability, other factors such as adherence with medication also play a role. In an analysis of 782 patients, visit-to-visit variability in LDL-C was strongly associated with statin non-adherence (odds ratio: 3.4; 95% CI: 1.7 to 7.1). However, in our analyses, LDL-C variability was an independent predictor of events even after controlling for statin non-adherence. In addition, visit-to-visit LDL-C variability may be important in patients receiving intermittent statin therapy. Alternative dosing schedules such as a few times per week, every other day, or even once per week have been investigated as methods to reduce myalgias and yet achieve efficacy in lowering LDL-C. Intermittent statin therapy, especially with longer-acting agents such as rosuvastatin or atorvastatin, is used in patients who are intolerant to daily statin therapy and has been shown to result in significant LDL-C reduction, although variability was not reported in these retrospective studies. The Canadian Working Group has recommended intermittent therapy for suspected statin intolerance. However, it remains unknown whether intermittent statin dosage provides the same cardiovascular protection as does daily statin therapy. The results of the present study are interesting with regard to monoclonal antibodies to PCSK-9 because the visit-to-visit variability with a once–per-month injection could be substantial. In the LAPLACE-TIMI 57 trial (LDL-C Assessment With PCSK9 monoclonaL Antibody Inhibition Combined With Statin therapy-Thrombolysis In Myocardial Infarction 57), the LDL-C variability was less when the medication was dosed every 2 weeks rather than every 4 weeks. However, whether it affects clinical outcomes must be tested in future trials.
The mechanism linking increased LDL-C variability to an increased risk of cardiovascular events is unknown, but there are several hypotheses. Statins stabilize plaque mainly (but not exclusively) by a cholesteroldependent mechanism, reducing the cholesterol content of plaque. Lipid lowering in turn inhibits inflammation and decreases collagenolytic activity and thrombotic potential. In addition, the cholesterolindependent action of statins through alterations in the function of G proteins also contributes to their anti-inflammatory and antithrombotic actions. LDL-C variability may cause instability at the vascular wall as a result of variability in lipid efflux mechanism (i.e., impair the cholesterol-dependent mechanism of plaque stabilization) and thus increase the potential for plaque vulnerability and rupture, thereby increasing the risk of cardiovascular events. Another potential mechanism of this increased risk is perhaps that LDL-C variability is an epiphenomenon of other systemic conditions that increase cardiovascular risk. It is possible that patients with systemic conditions leading to generalized frailty might have higher variability of multiple biological parameters and increased risk caused by several pathologic mechanisms. Finally, poor adherence to medications may link LDL variability with increased risk of cardiovascular events. LDL variabilitywas an independent predictor of events even after controlling for medication adherence. However, adherence was measured by means of pill counts without testing the "taking compliance" (i.e., whether a medication was actually taken) by use of drug levels. Further studies are needed to test this hypothesis.
Our data are derived from a randomized trial in which the visit-to-visit LDL-C variability probably is less than in real-world patients. Despite this, LDL-C variability measurements were strong and independent predictors of cardiovascular events. We did not have data on other factors that could result in higher LDL-C variability, including contents and proximity to the last meal. However, all lipid parameters in the TNT trial were measured in a fasting state, thus reducing the variability caused by proximity of the last meal. In addition, the results were not consistently seen across all measurements of LDL-C variability, but the results were largely similar. Moreover, variability measurements that are less sensitive to mean LDL levels such as SD and ASV produced largely consistent results.
Discussion
The results of this study indicate that visit-to-visit LDL-C variability is a powerful and independent predictor of any coronary event, any cardiovascular event, death, MI, and stroke, independent of treatment effect and achieved LDL-C levels (Central Illustration). In the adjusted model, each 1-SD increase in LDL-C variability (as measured by ASV) increased the risk of any coronary event by 16%, any cardiovascular event by 11%, death by 23%, MI by 10%, and stroke by 17%, independent of statin dose and achieved LDL-C levels. The association was significant even after controlling for treatment adherence.
(Enlarge Image)
Central Illustration.
Visit-to-Visit LDL-C Variability and Outcomes
Visit-to-visit LDL-C variability was defined as variability in LDL-C values between visits, on the basis of 9,572 patients from the TNT trial. LDL-C variability measured from 3 months onward into random assignment because this was the relatively steady phase in LDL-C after the initial decrease. CV = cardiovascular; LDL-C = low-density lipoprotein cholesterol; MI = myocardial infarction.
Statins and Cardiovascular Outcomes
Randomized trials, observational studies, andmeta-analyses have shown a significant benefit of statins for primary prevention of cardiovascular events as well as for secondary prevention. The results from these studies indicate that lowering of LDL-C by 1 mmol/l (approximately 39 mg/dl) with a statin reduces the incidence of major vascular events by approximately 20%. The standard statin regimen reduces LDL-C by approximately 30%, with more intensive statin regiment reducing this level by approximately 50%. In addition to a reduction in LDL-C, other pleotropic effects such as anti-inflammatory properties, plaque stabilization, and others appear to contribute to the significant benefit of statin therapy. It is therefore not surprising that statins are the mainstay for prevention and treatment of patients with CAD and are endorsed by major national and international guidelines. Despite this, there remains a residual risk of cardiovascular events even in patients receiving an intensive statin regimen. In the TNT trial, although intensive statin treatment with atorvastatin 80 mg/day reduced cardiovascular events when compared with atorvastatin 10 mg/day, the residual risk of major cardiovascular events was 8.7%, death was 5.7%, MI was 4.9%, and stroke was 2.3%.
Visit-to-visit variability in blood pressure is an independent predictor of adverse cardiovascular events, which suggests that a more uniform/less variable blood pressure is desirable. This is true despite that fact that there is variability in blood pressure measurement with time of day and with stress, activity, and emotions. However, it is not known if the same is applicable to LDL-C control. In the present study, we measured variability in the LDL-C levels from 3 months after the initial decrease onward into random assignment because this was the period in which the LDL-C levels in the 2 treatment arms were relatively stable. The results of the present study indicate a strong and independent effect of visit-to-visit variability measurements on long-term cardiovascular outcomes. Each 1-SD increase in visit-to-visit variability in LDL-C was associated with a significant increase in any coronary event, any cardiovascular event, death, MI, and stroke, and this was independent of treatment effect and achieved LDL-C levels, which suggests that a more uniform and less variable visit-to-visit LDL-C is important. The results of the present study also indicate that visit-tovisit variability in LDL-C was lower with atorvastatin 80 mg/day when compared with atorvastatin 10 mg/day. It therefore lends credence to the American College of Cardiology/American Heart Association blood cholesterol guideline recommendation of moderate- to high-intensity statins in patients with atherothrombotic vascular disease, not only for a more robust reduction in LDL-C but also for less variability in LDL-C. Although the dose of statin was predictive of visit-to-visit LDL-C variability, other factors such as adherence with medication also play a role. In an analysis of 782 patients, visit-to-visit variability in LDL-C was strongly associated with statin non-adherence (odds ratio: 3.4; 95% CI: 1.7 to 7.1). However, in our analyses, LDL-C variability was an independent predictor of events even after controlling for statin non-adherence. In addition, visit-to-visit LDL-C variability may be important in patients receiving intermittent statin therapy. Alternative dosing schedules such as a few times per week, every other day, or even once per week have been investigated as methods to reduce myalgias and yet achieve efficacy in lowering LDL-C. Intermittent statin therapy, especially with longer-acting agents such as rosuvastatin or atorvastatin, is used in patients who are intolerant to daily statin therapy and has been shown to result in significant LDL-C reduction, although variability was not reported in these retrospective studies. The Canadian Working Group has recommended intermittent therapy for suspected statin intolerance. However, it remains unknown whether intermittent statin dosage provides the same cardiovascular protection as does daily statin therapy. The results of the present study are interesting with regard to monoclonal antibodies to PCSK-9 because the visit-to-visit variability with a once–per-month injection could be substantial. In the LAPLACE-TIMI 57 trial (LDL-C Assessment With PCSK9 monoclonaL Antibody Inhibition Combined With Statin therapy-Thrombolysis In Myocardial Infarction 57), the LDL-C variability was less when the medication was dosed every 2 weeks rather than every 4 weeks. However, whether it affects clinical outcomes must be tested in future trials.
LDL-C Variability and Adverse Outcomes
The mechanism linking increased LDL-C variability to an increased risk of cardiovascular events is unknown, but there are several hypotheses. Statins stabilize plaque mainly (but not exclusively) by a cholesteroldependent mechanism, reducing the cholesterol content of plaque. Lipid lowering in turn inhibits inflammation and decreases collagenolytic activity and thrombotic potential. In addition, the cholesterolindependent action of statins through alterations in the function of G proteins also contributes to their anti-inflammatory and antithrombotic actions. LDL-C variability may cause instability at the vascular wall as a result of variability in lipid efflux mechanism (i.e., impair the cholesterol-dependent mechanism of plaque stabilization) and thus increase the potential for plaque vulnerability and rupture, thereby increasing the risk of cardiovascular events. Another potential mechanism of this increased risk is perhaps that LDL-C variability is an epiphenomenon of other systemic conditions that increase cardiovascular risk. It is possible that patients with systemic conditions leading to generalized frailty might have higher variability of multiple biological parameters and increased risk caused by several pathologic mechanisms. Finally, poor adherence to medications may link LDL variability with increased risk of cardiovascular events. LDL variabilitywas an independent predictor of events even after controlling for medication adherence. However, adherence was measured by means of pill counts without testing the "taking compliance" (i.e., whether a medication was actually taken) by use of drug levels. Further studies are needed to test this hypothesis.
Study Limitations
Our data are derived from a randomized trial in which the visit-to-visit LDL-C variability probably is less than in real-world patients. Despite this, LDL-C variability measurements were strong and independent predictors of cardiovascular events. We did not have data on other factors that could result in higher LDL-C variability, including contents and proximity to the last meal. However, all lipid parameters in the TNT trial were measured in a fasting state, thus reducing the variability caused by proximity of the last meal. In addition, the results were not consistently seen across all measurements of LDL-C variability, but the results were largely similar. Moreover, variability measurements that are less sensitive to mean LDL levels such as SD and ASV produced largely consistent results.
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