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PCSK9 Inhibitor & Peripheral Artery Disease and
Venous Thromboembolic Events After Acute Coronary Syndrome
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Download the PDF here
2020
In patients with recent ACS [acute coronary syndrome] on intensive statin treatment, the risk of PAD events is substantial, related to levels of lipoprotein(a), and is reduced with PCSK9 inhibition with alirocumab. A mechanism of this effect may be alirocumab-induced reduction of lipoprotein(a) levels. Further study is required to confirm whether the risk of VTE is related to lipoprotein(a) concentration and modified by PCSK9 inhibition.....
There are 4 key findings from this prespecified analysis of the ODYSSEY OUTCOMES trial. First, despite a history of PAD in only 4.0% of the trial cohort, there was a substantial risk of PAD events including critical limb ischemia, limb revascularization, and amputation for ischemia......Second, the risk of PAD events was strongly associated with the baseline level of lipoprotein(a), a lipoprotein believed to have thrombogenic, atherogenic, and inflammatory properties......Third, in patients with recent ACS, alirocumab resulted in a relative risk reduction for major PAD events of more than 30%, with the absolute risk reduction most pronounced in those with a previous history of PAD.......Fourth, multivariable analysis indicates that on assigned treatment with alirocumab the risk of VTE or the combination of PAD and VTE events was inversely related to the magnitude of lipoprotein(a) reduction, but not to the magnitude of reduction of LDL-Ccorrected (Table (Table2).2). .......The current data point to a role of lipoprotein(a) in the pathogenesis of PAD events and possibly VTE, and suggest that lipoprotein(a) reduction may be a potential approach to reduce the risk of those events, particularly in patients with a previous history of PAD......Our findings suggest that PCSK9 inhibitors might mitigate the risk of VTE when added to intensive statin treatment in selected patients.
Discussion
There are 4 key findings from this prespecified analysis of the ODYSSEY OUTCOMES trial. First, despite a history of PAD in only 4.0% of the trial cohort, there was a substantial risk of PAD events including critical limb ischemia, limb revascularization, and amputation for ischemia. The absolute risk of those events was approximately 2% in the placebo group at 4 years. Only 1.1% of the trial cohort had a previous history of VTE. Nonetheless, the risk of VTE during the trial was notable, occurring in approximately 0.7% of the placebo group at 4 years. These findings indicate that despite intensive statin and antiplatelet therapy, patients with a recent ACS remain at elevated risk for further events involving the peripheral arteries or the venous circulation.
Second, the risk of PAD events was strongly associated with the baseline level of lipoprotein(a), a lipoprotein believed to have thrombogenic, atherogenic, and inflammatory properties. There was a nonsignificant trend toward an association of PAD events with the baseline level of LDL-Ccorrected, a parameter that estimates the cholesterol contained in low-density lipoprotein particles by algebraic correction for the cholesterol contained in lipoprotein(a), but ordinarily measured as LDL-C. Had there been a larger number of PAD events, it is possible that a significant association of PAD events with baseline LDL-Ccorrected might have been identified. The relatively small number of VTE events limited power to determine whether VTE risk was associated with baseline levels of either lipoprotein(a) or LDL-Ccorrected; nonetheless, the reduction in lipoprotein(a) under treatment with alirocumab was significantly associated with reduced risk of VTE.
Third, in patients with recent ACS, alirocumab resulted in a relative risk reduction for major PAD events of more than 30%, with the absolute risk reduction most pronounced in those with a previous history of PAD. This finding is consistent with the effect of evolocumab on PAD events in patients with chronic atherosclerotic cardiovascular disease.30 The point estimates for relative effects of alirocumab on VTE and PAD events were similar, but as a result of the smaller number of VTE events the effect on that end point was not significant. Nonetheless, the likelihood of a true biological effect of alirocumab on both PAD and VTE events is strengthened by the fact that each type of component event (critical limb ischemia, limb revascularization or amputation, deep vein thrombosis, and pulmonary embolism) was numerically less frequent in the alirocumab group than in the placebo group.
Fourth, multivariable analysis indicates that on assigned treatment with alirocumab the risk of VTE or the combination of PAD and VTE events was inversely related to the magnitude of lipoprotein(a) reduction, but not to the magnitude of reduction of LDL-Ccorrected (Table (Table2).2). The latter observation does not necessarily indicate that levels of LDL-Ccorrected have no impact on the risk of PAD or VTE events, because baseline LDL-Ccorrected levels were already reduced by statin therapy in 96% of patients and intensive statin therapy in 87% of patients, and nearly all patients achieved a further, substantial reduction in LDL-Ccorrected with alirocumab. Nonetheless, the findings suggest centrality of lipoprotein(a) reduction in the efficacy of alirocumab to reduce the risk of PAD or VTE events. Patients with high versus low baseline levels of lipoprotein(a) had substantial versus minimal absolute reductions in lipoprotein(a) with alirocumab, while similar absolute reductions in LDL-Ccorrected were observed in both categories. Alirocumab reduced the risk of PAD or VTE events in the former category, but not the latter (Figure (Figure33 and Table III in the Data Supplement). Conversely, patients with higher versus lower baseline levels of LDL-Ccorrected had larger versus smaller absolute reductions in LDL-Ccorrected with alirocumab, without an apparent gradient of relative or absolute reduction in the risk of PAD or VTE events.
The current data point to a role of lipoprotein(a) in the pathogenesis of PAD events and possibly VTE, and suggest that lipoprotein(a) reduction may be a potential approach to reduce the risk of those events, particularly in patients with a previous history of PAD. The findings are consistent with data from the FOURIER trial, which showed that the PCSK9 inhibitor evolocumab reduced the risk of major PAD events.30 This present report complements evolving data indicating that lipoprotein(a) levels are important determinants of the risk of coronary events, even on a background of statin treatment,36 and previous data from ODYSSEY OUTCOMES that the reduction in risk of a composite of coronary and cerebrovascular events was related to baseline lipoprotein(a) levels and their reduction with alirocumab.32
Our findings suggest that PCSK9 inhibitors might mitigate the risk of VTE when added to intensive statin treatment in selected patients. However, the analysis is limited by a relatively small number of patients with VTE. The JUPITER trial (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin) provides a precedent for modification of VTE risk with a lipid-lowering intervention.23 However, in that trial, an effect of rosuvastatin to reduce VTE did not appear to depend on LDL-C levels, rosuvastatin did not affect lipoprotein(a) levels,37 all patients had elevated C-reactive protein at entry, and the possibility of an anti-inflammatory effect was raised. To date, a direct anti-inflammatory effect of PCSK9 inhibitors has not been identified. Defining the role of lipoprotein(a) in the pathogenesis of VTE and the potential for PCSK9 inhibitors to modify VTE risk will require further prospective investigation.
Limitations of the present analysis include the fact that PAD events and VTE were investigator-reported. Adjudication of events might have enhanced contrast between randomized treatment groups. The ODYSSEY OUTCOMES trial was not powered to detect effects of randomized treatment on PAD events or VTE; future studies could be designed specifically for this purpose. Lipoprotein(a) was measured with a mass concentration assay. Use of a molar concentration assay might have refined our findings.38
Conclusions
In patients with recent ACS on intensive statin treatment, the risk of PAD events is substantial, related to levels of lipoprotein(a), and is reduced with PCSK9 inhibition with alirocumab. A mechanism of this effect may be alirocumab-induced reduction of lipoprotein(a) levels. Further study is required to confirm whether the risk of VTE is related to lipoprotein(a) concentration and modified by PCSK9 inhibition.
INTRODUCTION
Peripheral artery disease (PAD) affects more than 200 million individuals worldwide,1 has a prevalence exceeding 10% among adults in the United States,2 is associated with a high risk of cardiovascular events,3 and extracts a large toll from patients’ quality of life and society’s healthcare costs.4,5
Smoking, diabetes mellitus, and hypertension are the strongest risk factors for PAD, but dyslipidemia may be contributory. An association between elevated levels of triglyceride-rich lipoproteins or low-density lipoprotein cholesterol (LDL-C) and incident PAD has been found in some, but not all, analyses.6-11 Lipoprotein(a), a low-density lipoprotein whose levels are primarily under genetic control, has atherogenic, proinflammatory, and thrombogenic properties.12 Most observational cohort studies indicate an association of elevated lipoprotein(a) with incident PAD.13-16 In addition, the progression of chronic obstructive PAD to critical limb ischemia is influenced by thrombophilic factors,17 possibly including levels of lipoprotein(a).18,19
Venous thromboembolism (VTE) and PAD events may share common pathophysiology related to thrombophilia and inflammation.20-22 VTE does not appear to be associated with levels of LDL-C.23 However, there are conflicting data regarding an association of VTE with concentration or genetic variants of lipoprotein(a).24-27
Statins reduce levels of LDL-C and triglycerides but not lipoprotein(a). Statins also improve exercise capacity in patients with PAD.28 Although observational data suggest that statins may reduce major adverse limb events including critical limb ischemia, revascularization, and amputation,29 there is a dearth of corroborating evidence from randomized placebo-controlled trials. In one large, randomized placebo-controlled trial, rosuvastatin reduced VTE, but the effect was unrelated to levels of LDL-C.23
Inhibitors of PCSK9 (proprotein convertase subtilisin/kexin type 9) reduce LDL-C and lipoprotein(a) levels, with a modest effect on triglycerides. In the FOURIER trial (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk), the PCSK9 inhibitor evolocumab reduced major adverse limb events compared with placebo on a background of statin treatment.30 However, the relationship of this effect to evolocumab-induced changes in individual lipoproteins was not assessed. It is important that the effects of PCSK9 inhibitors on VTE have not been evaluated.
The ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome) compared the PCSK9 inhibitor alirocumab with placebo in patients with recent acute coronary syndromes (ACS) on intensive statin treatment.31 The primary outcome of major coronary heart disease events and ischemic stroke was reduced with the PCSK9 inhibitor alirocumab, with the benefit related to reductions in levels of both LDL-C and lipoprotein(a),32 and with a particularly pronounced benefit for this outcome in patients with PAD.33 In this prespecified analysis, we examined the relationship of PAD and VTE events to baseline lipoprotein levels, the effects of treatment with alirocumab or placebo on PAD or VTE events, and the relation of those treatment effects to lipoprotein levels.
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Role of Lipoprotein(a) and Modification by Alirocumab: Prespecified Analysis of the ODYSSEY OUTCOMES Randomized Clinical Trial
2020 May 19
Background:
Patients with acute coronary syndrome are at risk for peripheral artery disease (PAD) events and venous thromboembolism (VTE). PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors reduce lipoprotein(a) and low-density lipoprotein cholesterol (LDL-C) levels. Our objective was to ascertain whether PCSK9 inhibition reduces the risk of PAD events or VTE after acute coronary syndrome, and if such effects are related to levels of lipoprotein(a) or LDL-C.
Methods:
This was a prespecified analysis of the ODYSSEY OUTCOMES randomized clinical trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome), which was conducted in 18 924 patients with recent acute coronary syndrome on intensive or maximum-tolerated statin treatment who were randomized to the PCSK9 inhibitor alirocumab or placebo. In a prespecified analysis, PAD events (critical limb ischemia, limb revascularization, or amputation for ischemia) and VTE (deep vein thrombosis or pulmonary embolism) were assessed. LDL-C was corrected (LDL-Ccorrected) for cholesterol content in lipoprotein(a).
Results:
At baseline, median lipoprotein(a) and LDL-Ccorrected were 21 and 75 mg/dL, respectively; with alirocumab, median relative reductions were 23.5% and 70.6%, respectively. PAD events and VTE occurred in 246 and 92 patients, respectively. In the placebo group, risk of PAD events was related to baseline quartile of lipoprotein(a) (Ptrend=0.0021), and tended to associate with baseline quartile of LDL-Ccorrected (Ptrend=0.06); VTE tended to associate with baseline quartile of lipoprotein(a) (Ptrend=0.06), but not LDL-Ccorrected (Ptrend=0.85). Alirocumab reduced risk of PAD events (hazard ratio [HR], 0.69 [95% CI, 0.54-0.89]; P=0.004), with nonsignificantly fewer VTE events (HR, 0.67 [95% CI, 0.44-1.01]; P=0.06). Reduction in PAD events with alirocumab was associated with baseline quartile of lipoprotein(a) (Ptrend=0.03), but not LDL-Ccorrected (Ptrend=0.50). With alirocumab, the change from baseline to Month 4 in lipoprotein(a), but not LDL-Ccorrected, was associated with the risk of VTE and the composite of VTE and PAD events.
Conclusions:
In statin-treated patients with recent acute coronary syndrome, risk of PAD events is related to lipoprotein(a) level and is reduced by alirocumab, particularly among those with high lipoprotein(a). Further study is required to confirm whether risk of VTE is related to lipoprotein(a) level and its reduction with alirocumab.
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