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Lipoprotein(a) apheresis in patients with peripheral arterial disease: rationale and clinical results

Lipoprotein(a) apheresis in patients with peripheral arterial disease: rationale and clinical... Patients with symptomatic peripheral arterial disease (PAD) are at a very high risk of cardiovascular morbidity and mortality. Elevated lipoprotein(a) levels have been shown to be a risk factor for coronary artery disease (CAD) and stroke. More recently elevated lipoprotein(a) levels have also been demonstrated to be associated with prevalent and incident PAD, and even may be a stronger risk factor for PAD compared with CAD. Lipoprotein apheresis is currently the only efficient way to lower lipoprotein(a) levels. Lipoprotein(a) apheresis has been shown to reduce major coronary events in patients with CAD. There is increasing evidence that lipoprotein(a) apheresis also reduces the rate of major adverse limb events such as peripheral revascularizations and amputations in PAD patients, and improves symptoms of PAD such as pain on exertion. This review summarizes the current knowledge on the clinical role of lipoprotein(a) for PAD and the disease-specific effect of lipoprotein(a) apheresis, and suggests indications for screening for and treating of elevated lipoprotein(a) levels in patients with PAD. Keywords Peripheral arterial disease · Intermittent claudication · Critical limb ischemia · Atherosclerosis · Cardiovascular prevention Introduction extremities arterial disease, the most frequent manifestation of PAD [3, 4]. Peripheral arterial disease (PAD), coronary artery disease The fate of patients with PAD is determined by the prog- (CAD) and cerebrovascular disease (CVD) are different nosis of the affected extremity and by the total cardiovascu- manifestations of atherosclerotic vascular disease. The lar prognosis. Patients with intermittent claudication rarely whole spectrum of atherosclerotic cardiovascular diseases progress to critical limb ischemia and are at low risk for am- shares common cardiovascular risk factors such as smok- putation, which is estimated to be at 2 to 4% within 5 years ing, diabetes, hypertension and hyperlipidemia and require after initial presentation. These patients, however, are ten identical risk factor management for primary and secondary times more likely to suffer a non-fatal or fatal cardiac or prevention [1]. The term PAD is not well defined and some- cerebrovascular event [5]. Patients that initially present with times used to summarize diseases of all extracranial and critical limb ischemia, i. e. with rest pain and/or ischemic extracoronary arteries including carotid artery disease, foot lesions, are a different entity with both a very high one mesenteric and renal artery disease, as well as upper and year mortality and amputation rate up to 30% each. lower extremities arterial disease [2]. Most often, and also Besides the above mentioned predominant risk factors in this paper, the term PAD is used synonymously to lower elevated levels of lipoprotein(a) have been identified as an important additional atherothrombotic agent that increases the risk of developing PAD and adversely influences the This article is part of the special issue “Lp(a) – Update 2018” prognosis of patients with established PAD patients quoad extremitatem and quoad vitam [6]. This review will sum- Norbert Weiss norbert.weiss@ukdd.de marize and discuss current knowledge about the association and putative causal role of lipoprotein(a) for PAD and the University Center for Vascular Medicine and Department effect of lipoprotein(a) lowering by lipoprotein apheresis of Medicine III—Section Angiology, University Hospital and PAD itself and overall cardiovascular prognosis of PAD Carl Gustav Carus, Technische Universität Dresden, patients. Fetscherstr. 74, 01307 Dresden, Germany Department of Medicine III—Lipidology and Center for Extracorporeal Treatment, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany K 40 N. Weiss, U. Julius Peripheral arterial disease is a marker for 404 post-MI patients who also had PAD [10]. During three very high cardiovascular risk years of follow-up the composite endpoint of cardiovascu- lar death, myocardial infarction and stroke was significantly Current guidelines consider clinically manifest PAD as more frequent in the patients with PAD (19.3%) compared a risk equivalent to manifest CAD requiring identical treat- with the patients without PAD (8.4%, unadjusted hazard ment strategies and goals with respect to atherosclerotic ratio 2.46, adjusted hazard ratio 1.6). risk factor management [1]. The overall cardiovascular risk These two recent randomized trials emphasize the higher associated with PAD, however, still seems to be underes- ischemic risk in patients with symptomatic PAD with and timated as there is undertreatment of PAD compared with without concomitant CAD compared to patients with CAD CAD patients with lipid-lowering, anti-hypertensive and without PAD even in patients who are under optimal con- antiplatelet drugs [7]. Recent data show that patients with ventional medical treatment. This suggests that the higher symptomatic PAD even without concomitant CAD carry atherosclerotic burden in PAD compared with CAD and/or a higher risk of death and cardiovascular events compared differences in the impact of different atherosclerotic risk with patients with CAD without clinically manifest PAD. factors in different manifestations of the disease may be Pereg and colleagues [8] prospectively followed a co- responsible for the higher cardiovascular event rate in PAD hort of nearly 10,000 patients for up to 10 years (mean patients. follow-up 5.6 ± 2.3 years) who had undergone their first clinically driven coronary intervention (82.8% of patients) or peripheral vascular intervention (17.2% of patients). The Elevated lipoprotein(a) levels are a risk factor for peripheral arterial disease PAD patients had a significantly worse long-term progno- sis with a significantly increased all-cause mortality com- pared with the CAD patients (unadjusted hazard ratio 2.95, Several case–control studies proposed an association be- multivariately adjusted hazard ratio 1.86). This observation tween elevated lipoprotein(a) levels and the risk of suffering cannot be solely explained by undertreatment of PAD pa- from PAD. tients. Randomized controlled trials of novel lipid-lowering In the “Linz Peripheral Arterial Disease” (LIPAD) study or antiplatelet drugs, in which PAD and CAD patients were from Lower Austria 213 patients with symptomatic PAD included and in which all patients received optimal conven- were matched to 213 controls for sex, age, and presence of tional treatment, confirmed the higher cardiovascular risk diabetes [11]. Lipoprotein(a) concentrations were measured of PAD patients. by a double-antibody enzyme-linked immunosorbent assay The “Further Cardiovascular Outcomes Research with (ELISA), and apolipoprotein(a) isoform by sodium dodecyl PCSK9 Inhibition in patients with Elevated Risk” sulfate (SDS) agarose gel electrophoresis under reducing (FOURIER) trial was a randomized trial of the propro- conditions. Low molecular weight isoforms were defined tein convertase subtilisin/kexin type 9 (PCSK9) inhibitor as at least one allele with 22 kringle-IV repeats. PAD pa- evolocumab versus placebo in nearly 28,000 patients with tients compared with controls showed significantly higher stable atherosclerotic vascular disease who were on optimal medium lipoprotein(a) serum concentrations and a higher medical therapy including high-dose statin. The trial in- frequency of low molecular weight apolipoprotein(a) phe- cluded 3642 patients with symptomatic PAD (1505 with no notype. After adjustment for potential confounding factors, prior myocardial infarction or stroke) and 23,922 patients lipoprotein(a) concentrations above the 75th percentile with prior myocardial infarction of stroke without known of the entire cohort were a significant predictor of PAD PAD [9]. In the placebo group, the 2.5-year event rate of with an odds ratio of 3.73, as was the low molecular the composite endpoint of cardiovascular death, myocar- weight apolipoprotein(a) phenotype (odds ratio 2.21). This dial infarction, stroke, hospitalization for unstable angina, association was consistently confirmed in several other or coronary revascularization was significantly higher in case–control or cross sectional cohort studies in different patients with symptomatic PAD (16.8%) compared with populations including in total more than 10,000 subjects. patients without PAD (12.1%, adjusted hazard ratio 1.57). The “Cardiovascular Disease in Intermittend Claudiation” “Prevention of Cardiovascular Events in Patients with (CAVASIC) and the “Kooperative Gesundheitsforschung in Prior Heart Attack Using Ticagrelor Compared to Placebo der Region Augsburg” (KORA F3 and KORA F4) studies on a Background of Aspirin-Thrombolysis in Myocardial included populations from southern Germany [12], a fur- Infarction 54” (PEGASUS TIMI 54) was a trial of dual an- ther cohort was studied in France [13], and the “Multi- tiplatelet therapy using ticagrelor in stable post-myocardial Ethnic Study of Atherosclerosis” (MESA) included nearly infarction (MI) patients. All patients received optimal med- 5000 European Americans, African Americans, Hispanic ical treatment of cardiovascular risk factors. The placebo Americans and Chinese Americans [14]. group included 6633 post-MI patients without PAD and K Lipoprotein(a) apheresis in patients with peripheral arterial disease: rationale and clinical results 41 The causality of elevated lipoprotein(a) for the develop- Prognostic impact of elevated lipoprotein(a) levels in patients with peripheral arterial ment of PAD was then strongly suggested by three prospec- tive cohort studies. disease A substudy of the “European Prospective Investigation into Cancer and Nutrition” prospective population study In patients with established symptomatic PAD elevated (EPIC-Norfolk) included 25,639 female and male inhabi- lipoprotein(a) levels also seem to be a risk factor for sub- tants of Norfolk, United Kingdom, aged between 29 and sequent arterial events. Sanchez Monoz-Torreo et al. [18] 79 years [15]. The baseline survey was performed between prospectively followed a Spanish cohort of 1503 outpa- 1993 and 1997. Patients were followed until 2008. Out- tients with symptomatic PAD for a mean of 36 months. comes were identified by linking a unique National Health During that time patients suffered from 122 myocardial Service number in the EPIC database with the East Nor- infarctions, 118 strokes, 58 lower limb amputations, and folk Health Authority database. Mortality and hospitaliza- 85 deaths. This event rate again indicates that patients tions for PAD and CAD were classified according to the with established PAD are at a very high cardiovascular respective International Classification of Diseases (ICD) and mortality risk. According to baseline lipoprotein(a) codes. During 212,981 person–years at risk 2365 CAD and levels patients were separated into tertiles. Patients having 596 PAD events occurred. Study participants in the highest lipoprotein(a) levels in the highest tertile above 50 mg/dL sex-specific lipoprotein(a) quartile had an about 2-fold in- compared with patients in the lowest tertile below 30 mg/dL creased hazard ratio for the developing of PAD compared to were shown to have an adjusted hazard ratio of 23.22 (95% study participants in the other lipoprotein(a) quartiles. The confidence interval 12.17–44.29) for suffering a myocardial hazard ratio remained largely unchanged after adjusting for infarction, of 64.52 (95% confidence interval 29.13–142.93) several putative confounding factors including low-density for suffering a stroke, of 22.75 (95% confidence interval lipoprotein(LDL)-cholesterol. Notably, the predictive value 9.25–55.97) for suffering a lower limb amputation, and of lipoprotein(a) levels in the highest quartile were higher of 32.92 (95% confidence interval 21.35–50.77) for any for PAD (adjusted hazard ratio 2.06) compared with CAD of these arterial events. These findings have to be con- (adjusted hazard ratio 1.33). firmed in additional cohorts but indicate the high ongoing The latter finding is consistent with data from the atherothrombotic risk of elevated lipoprotein(a) levels in prospective “Scottish Heart Health Extended Cohort” [16]. patients with established atherosclerotic vascular disease. This large prospective cohort recruited 15,737 healthy men and women across Scotland between 1984 and 1995, and Efficacy of lipoprotein(a) apheresis in followed them through 2009 for CAD and PAD diagnoses. patients with peripheral arterial disease The 20-year risk for PAD hospitalization and mortality was significantly determined by baseline lipoprotein(a) levels with an hazard ratio of 1.21. In contrast, baseline lipopro- A causal relationship between elevated lipoprotein(a) lev- tein(a) levels were not significantly predictive for CAD risk els and PAD that is strongly suggested by prospective in this cohort. cohort studies will finally be proven after lipoprotein(a) The above mentioned findings although apply to popu- lowering therapies have shown to reduce the incidence lations from other geographic origin, as baseline lipopro- and progression of PAD and other cardiovascular events tein(a) levels were also predictive for incident PAD during in PAD patients. There is no effective pharmacological 6-year follow-up in a sample of more than 1000 Italian treatment to lower lipoprotein(a) levels clinically avail- subjects over the age of 60 [17]. able at the moment, although RNA-targeted therapeutics Taken together the above mentioned data strongly sug- to reduce lipoprotein(a) levels already have successfully gest that elevated lipoprotein(a) levels increase the risk of completed phase II clinical trials [19]. Lipoprotein aphere- developing clinical relevant PAD that leads to hospitaliza- sis remains the only treatment option for patients with tion and mortality. Elevated lipoprotein(a) levels seem to be elevated lipoprotein(a) and progressive cardiovascular dis- a more important risk factor for PAD compared with CAD ease despite optimal medical treatment of all conventional (or stroke, the latter data not shown). cardiovascular risk factors. Lipoprotein apheresis has been shown to reduce the rate of cardiovascular events in pa- tients with established coronary artery disease associated with high lipoprotein(a) levels [20–23]. Published data on the efficacy of lipoprotein apheresis in patients with PAD and elevated lipoprotein(a) are sparse, although PAD is highly prevalent in patients that are treated by lipoprotein(a) apheresis. Among 90 patients who started K 42 N. Weiss, U. Julius lipoprotein apheresis due to progressive cardiovascular dis- apheresis also led to a rapid and sustained improvement of ease and either isolated elevated lipoprotein(a) levels or PAD symptoms in all patients. This is indicated by a sig- a combination of elevated lipoprotein(a) and low-density nificant reduction of the pain level from 7.0 ± 1.5 points at lipoprotein cholesterol levels between 2008 and 2013 pe- baseline to 1.6 ± 0.7 after one and 1.1 ± 0.4 after two years ripheral arterial disease was present in 44 and 53% of pa- of lipoprotein apheresis. Consistently, the mean walking tients, respectively [24]. Among the 170 patients in the distance increased from 87 ± 60 m at baseline gradually to “Prospective Lipoprotein(a) Apheresis Registry Pro(a)Life” 402 ± 119 after two years. This went along with a significant that represented around 60% of the German patients that increase in the resting ankle-brachial index in the affected were treated by lipoprotein(a) apheresis in 2011 [21]30 leg. lower limb peripheral arterial events had occurred in the Taken together these data show that lipoprotein aphere- two years before initiation of lipoprotein apheresis. sis rapidly and significantly improves symptoms of PAD The latter registry followed these 170 patients and com- such as pain during physical activity and the walking dis- pared the cardiovascular event rates before and after ini- tance and reduces the rate of clinically driven peripheral tiation of lipoprotein(a) apheresis. In addition to a signifi- revascularizations. cant reduction of major cardiovascular events including my- ocardial infarction, percutaneous coronary intervention and Conclusions coronary artery bypass grafting from 144 in the two years before to 31 in the two years after initiation of lipoprotein apheresis the rate of peripheral arterial events including Elevated lipoprotein(a) levels have been shown to be a risk peripheral arterial angioplasty, stenting or bypass surgery factor for the development of cardiovascular disease in the was reduced from 30 to 11, respectively. Furthermore, other coronary and cerebrovascular circulation. Although ran- non-coronary interventions such as carotid artery stenting domized controlled trials are missing and won’t be possible or surgery or renal artery angioplasty or stenting was re- to perform due to ethical reasons within the near future duced from 7 to 1, respectively [21]. longitudinal observational studies strongly suggest that the In a monocentric, retrospective, longitudinal cohort reduction of lipoprotein(a) levels by lipoprotein apheresis study 35 patients with isolated lipoprotein(a) elevation had significantly and clinical relevantly reduces the incidence been included, and the rate of cardiovascular events in the of cardiovascular events [20–23, 25]. There is increasing 6.8 ± 5.6 years before and 6.8 ± 4.9 years after initiation evidence from case–control studies, cross-sectional cohort of chronic lipoprotein apheresis was compared. Besides studies and longitudinal prospective cohort studies that el- a 90.4% reduction of major adverse cardiac events in- evated lipoprotein(a) levels are a risk factor for the devel- cluding cardiac death, non-lethal myocardial infarction, opment of PAD and for a worse clinical outcome in PAD coronary bypass surgery and percutaneous coronary inter- patients [11–18]. Furthermore, longitudinal observational ventions a reduction of peripheral vascular events from studies indicated that lipoprotein apheresis also reduces the 11 in the years before to 2 in the years after initiation of necessity for clinically driven revascularizations in patients lipoprotein apheresis could be observed [25]. with PAD [21, 23, 25–27]. Whether or not it also reduces Poller and coworkers [26, 27] prospectively followed the extremely high burden of overall cardiovascular morbid- 10 patients who were treated by lipoprotein apheresis due ity and mortality in PAD patients that is higher compared to symptomatic PAD that required a revascularization pro- with patients with isolated CAD [8, 9] has not been studied cedure, had elevated lipoprotein(a) levels above 60 mg/dL so far but seems to be biologically plausible. and were on sufficient treatment of all other cardiovascular Therefore it is good clinical practice that patients with risk factors. Outcome measures were the rate of clinically PAD and progressive disease despite control of all conven- driven revascularizations in the 12 months prior compared tional risk factors should be screened for elevated lipopro- with the 24 months after initiation of lipoprotein apheresis tein(a) levels. In addition patients with elevated lipopro- as well as the ankle-brachial blood pressure index, the walk- tein(a) levels and coronary or cerebrovascular atherosclero- ing distance determined by a standardized treadmill test, as sis should also be screened for the presence of PAD, either well as subjective grading of the mean pain level during symptomatic or asymptomatic, as patients with polyvascu- everyday physical activity on a 10-point visual analogue lar disease in the coronary and peripheral circulation are at scale (the higher the score the worse the pain). Consis- higher risk compared to patients with isolated CAD [10]. tent with the above mentioned study, the study also showed PAD patients with elevated lipoprotein(a) levels and pro- a significant reduction of clinical driven revascularizations gressive disease as indicated by recurrent clinical events re- from 35 procedures during 120 patient–months in the year quiring revascularization or progression of the disease stage before to 2 procedures per 229 patient–months in the two from asymptomatic to intermittent claudication or critical years after initiation of lipoprotein apheresis. Lipoprotein limb ischemia or from intermittent claudication to critical K Lipoprotein(a) apheresis in patients with peripheral arterial disease: rationale and clinical results 43 3. 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Curr Treat Options Cardiovasc Med 19(7):48. Lipoprotein Apheresis on Cardiovascular Outcomes” (Mul- https://doi.org/10.1007/s11936-017-0549-z 7. Zeymer U, Parhofer KG, Pittrow D, Binz C, Schwertfeger M, tiSelect) [29]. Limbourg T, Röther J (2009) Risk factor profile, management Conflict of interest N. Weiss received speaker’s honoraria from Fre- and prognosis of patients with peripheral arterial disease with or senius Medical Care. U. Julius received speaker’s honoraria from without coronary artery disease: results of the prospective Ger- Kaneka, Diamed, Fresenius Medical Care. Both serve in the adjudica- man REACH registry cohort. Clin Res Cardiol 98(4):249–256. tion committee of the MultiSelect trial sponsored by Kaneka. https://doi.org/10.1007/s00392-009-0754-1 8. 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Atheroscler Suppl30:180–186. https://doi.org/10. ling D, Breitenberger P, Maerz W, Lehmacher W, Heibges A, 1016/j.atherosclerosissup.2017.05.009 Klingel R, Pro(a)LiFe Study Group (2013) Lipoprotein aphere- sis in patients with maximally tolerated lipid-lowering therapy, http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Research in Cardiology Supplements Springer Journals

Lipoprotein(a) apheresis in patients with peripheral arterial disease: rationale and clinical results

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Medicine & Public Health; Cardiology; Internal Medicine; Angiology; Cardiac Surgery; Diagnostic Radiology
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Abstract

Patients with symptomatic peripheral arterial disease (PAD) are at a very high risk of cardiovascular morbidity and mortality. Elevated lipoprotein(a) levels have been shown to be a risk factor for coronary artery disease (CAD) and stroke. More recently elevated lipoprotein(a) levels have also been demonstrated to be associated with prevalent and incident PAD, and even may be a stronger risk factor for PAD compared with CAD. Lipoprotein apheresis is currently the only efficient way to lower lipoprotein(a) levels. Lipoprotein(a) apheresis has been shown to reduce major coronary events in patients with CAD. There is increasing evidence that lipoprotein(a) apheresis also reduces the rate of major adverse limb events such as peripheral revascularizations and amputations in PAD patients, and improves symptoms of PAD such as pain on exertion. This review summarizes the current knowledge on the clinical role of lipoprotein(a) for PAD and the disease-specific effect of lipoprotein(a) apheresis, and suggests indications for screening for and treating of elevated lipoprotein(a) levels in patients with PAD. Keywords Peripheral arterial disease · Intermittent claudication · Critical limb ischemia · Atherosclerosis · Cardiovascular prevention Introduction extremities arterial disease, the most frequent manifestation of PAD [3, 4]. Peripheral arterial disease (PAD), coronary artery disease The fate of patients with PAD is determined by the prog- (CAD) and cerebrovascular disease (CVD) are different nosis of the affected extremity and by the total cardiovascu- manifestations of atherosclerotic vascular disease. The lar prognosis. Patients with intermittent claudication rarely whole spectrum of atherosclerotic cardiovascular diseases progress to critical limb ischemia and are at low risk for am- shares common cardiovascular risk factors such as smok- putation, which is estimated to be at 2 to 4% within 5 years ing, diabetes, hypertension and hyperlipidemia and require after initial presentation. These patients, however, are ten identical risk factor management for primary and secondary times more likely to suffer a non-fatal or fatal cardiac or prevention [1]. The term PAD is not well defined and some- cerebrovascular event [5]. Patients that initially present with times used to summarize diseases of all extracranial and critical limb ischemia, i. e. with rest pain and/or ischemic extracoronary arteries including carotid artery disease, foot lesions, are a different entity with both a very high one mesenteric and renal artery disease, as well as upper and year mortality and amputation rate up to 30% each. lower extremities arterial disease [2]. Most often, and also Besides the above mentioned predominant risk factors in this paper, the term PAD is used synonymously to lower elevated levels of lipoprotein(a) have been identified as an important additional atherothrombotic agent that increases the risk of developing PAD and adversely influences the This article is part of the special issue “Lp(a) – Update 2018” prognosis of patients with established PAD patients quoad extremitatem and quoad vitam [6]. This review will sum- Norbert Weiss norbert.weiss@ukdd.de marize and discuss current knowledge about the association and putative causal role of lipoprotein(a) for PAD and the University Center for Vascular Medicine and Department effect of lipoprotein(a) lowering by lipoprotein apheresis of Medicine III—Section Angiology, University Hospital and PAD itself and overall cardiovascular prognosis of PAD Carl Gustav Carus, Technische Universität Dresden, patients. Fetscherstr. 74, 01307 Dresden, Germany Department of Medicine III—Lipidology and Center for Extracorporeal Treatment, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany K 40 N. Weiss, U. Julius Peripheral arterial disease is a marker for 404 post-MI patients who also had PAD [10]. During three very high cardiovascular risk years of follow-up the composite endpoint of cardiovascu- lar death, myocardial infarction and stroke was significantly Current guidelines consider clinically manifest PAD as more frequent in the patients with PAD (19.3%) compared a risk equivalent to manifest CAD requiring identical treat- with the patients without PAD (8.4%, unadjusted hazard ment strategies and goals with respect to atherosclerotic ratio 2.46, adjusted hazard ratio 1.6). risk factor management [1]. The overall cardiovascular risk These two recent randomized trials emphasize the higher associated with PAD, however, still seems to be underes- ischemic risk in patients with symptomatic PAD with and timated as there is undertreatment of PAD compared with without concomitant CAD compared to patients with CAD CAD patients with lipid-lowering, anti-hypertensive and without PAD even in patients who are under optimal con- antiplatelet drugs [7]. Recent data show that patients with ventional medical treatment. This suggests that the higher symptomatic PAD even without concomitant CAD carry atherosclerotic burden in PAD compared with CAD and/or a higher risk of death and cardiovascular events compared differences in the impact of different atherosclerotic risk with patients with CAD without clinically manifest PAD. factors in different manifestations of the disease may be Pereg and colleagues [8] prospectively followed a co- responsible for the higher cardiovascular event rate in PAD hort of nearly 10,000 patients for up to 10 years (mean patients. follow-up 5.6 ± 2.3 years) who had undergone their first clinically driven coronary intervention (82.8% of patients) or peripheral vascular intervention (17.2% of patients). The Elevated lipoprotein(a) levels are a risk factor for peripheral arterial disease PAD patients had a significantly worse long-term progno- sis with a significantly increased all-cause mortality com- pared with the CAD patients (unadjusted hazard ratio 2.95, Several case–control studies proposed an association be- multivariately adjusted hazard ratio 1.86). This observation tween elevated lipoprotein(a) levels and the risk of suffering cannot be solely explained by undertreatment of PAD pa- from PAD. tients. Randomized controlled trials of novel lipid-lowering In the “Linz Peripheral Arterial Disease” (LIPAD) study or antiplatelet drugs, in which PAD and CAD patients were from Lower Austria 213 patients with symptomatic PAD included and in which all patients received optimal conven- were matched to 213 controls for sex, age, and presence of tional treatment, confirmed the higher cardiovascular risk diabetes [11]. Lipoprotein(a) concentrations were measured of PAD patients. by a double-antibody enzyme-linked immunosorbent assay The “Further Cardiovascular Outcomes Research with (ELISA), and apolipoprotein(a) isoform by sodium dodecyl PCSK9 Inhibition in patients with Elevated Risk” sulfate (SDS) agarose gel electrophoresis under reducing (FOURIER) trial was a randomized trial of the propro- conditions. Low molecular weight isoforms were defined tein convertase subtilisin/kexin type 9 (PCSK9) inhibitor as at least one allele with 22 kringle-IV repeats. PAD pa- evolocumab versus placebo in nearly 28,000 patients with tients compared with controls showed significantly higher stable atherosclerotic vascular disease who were on optimal medium lipoprotein(a) serum concentrations and a higher medical therapy including high-dose statin. The trial in- frequency of low molecular weight apolipoprotein(a) phe- cluded 3642 patients with symptomatic PAD (1505 with no notype. After adjustment for potential confounding factors, prior myocardial infarction or stroke) and 23,922 patients lipoprotein(a) concentrations above the 75th percentile with prior myocardial infarction of stroke without known of the entire cohort were a significant predictor of PAD PAD [9]. In the placebo group, the 2.5-year event rate of with an odds ratio of 3.73, as was the low molecular the composite endpoint of cardiovascular death, myocar- weight apolipoprotein(a) phenotype (odds ratio 2.21). This dial infarction, stroke, hospitalization for unstable angina, association was consistently confirmed in several other or coronary revascularization was significantly higher in case–control or cross sectional cohort studies in different patients with symptomatic PAD (16.8%) compared with populations including in total more than 10,000 subjects. patients without PAD (12.1%, adjusted hazard ratio 1.57). The “Cardiovascular Disease in Intermittend Claudiation” “Prevention of Cardiovascular Events in Patients with (CAVASIC) and the “Kooperative Gesundheitsforschung in Prior Heart Attack Using Ticagrelor Compared to Placebo der Region Augsburg” (KORA F3 and KORA F4) studies on a Background of Aspirin-Thrombolysis in Myocardial included populations from southern Germany [12], a fur- Infarction 54” (PEGASUS TIMI 54) was a trial of dual an- ther cohort was studied in France [13], and the “Multi- tiplatelet therapy using ticagrelor in stable post-myocardial Ethnic Study of Atherosclerosis” (MESA) included nearly infarction (MI) patients. All patients received optimal med- 5000 European Americans, African Americans, Hispanic ical treatment of cardiovascular risk factors. The placebo Americans and Chinese Americans [14]. group included 6633 post-MI patients without PAD and K Lipoprotein(a) apheresis in patients with peripheral arterial disease: rationale and clinical results 41 The causality of elevated lipoprotein(a) for the develop- Prognostic impact of elevated lipoprotein(a) levels in patients with peripheral arterial ment of PAD was then strongly suggested by three prospec- tive cohort studies. disease A substudy of the “European Prospective Investigation into Cancer and Nutrition” prospective population study In patients with established symptomatic PAD elevated (EPIC-Norfolk) included 25,639 female and male inhabi- lipoprotein(a) levels also seem to be a risk factor for sub- tants of Norfolk, United Kingdom, aged between 29 and sequent arterial events. Sanchez Monoz-Torreo et al. [18] 79 years [15]. The baseline survey was performed between prospectively followed a Spanish cohort of 1503 outpa- 1993 and 1997. Patients were followed until 2008. Out- tients with symptomatic PAD for a mean of 36 months. comes were identified by linking a unique National Health During that time patients suffered from 122 myocardial Service number in the EPIC database with the East Nor- infarctions, 118 strokes, 58 lower limb amputations, and folk Health Authority database. Mortality and hospitaliza- 85 deaths. This event rate again indicates that patients tions for PAD and CAD were classified according to the with established PAD are at a very high cardiovascular respective International Classification of Diseases (ICD) and mortality risk. According to baseline lipoprotein(a) codes. During 212,981 person–years at risk 2365 CAD and levels patients were separated into tertiles. Patients having 596 PAD events occurred. Study participants in the highest lipoprotein(a) levels in the highest tertile above 50 mg/dL sex-specific lipoprotein(a) quartile had an about 2-fold in- compared with patients in the lowest tertile below 30 mg/dL creased hazard ratio for the developing of PAD compared to were shown to have an adjusted hazard ratio of 23.22 (95% study participants in the other lipoprotein(a) quartiles. The confidence interval 12.17–44.29) for suffering a myocardial hazard ratio remained largely unchanged after adjusting for infarction, of 64.52 (95% confidence interval 29.13–142.93) several putative confounding factors including low-density for suffering a stroke, of 22.75 (95% confidence interval lipoprotein(LDL)-cholesterol. Notably, the predictive value 9.25–55.97) for suffering a lower limb amputation, and of lipoprotein(a) levels in the highest quartile were higher of 32.92 (95% confidence interval 21.35–50.77) for any for PAD (adjusted hazard ratio 2.06) compared with CAD of these arterial events. These findings have to be con- (adjusted hazard ratio 1.33). firmed in additional cohorts but indicate the high ongoing The latter finding is consistent with data from the atherothrombotic risk of elevated lipoprotein(a) levels in prospective “Scottish Heart Health Extended Cohort” [16]. patients with established atherosclerotic vascular disease. This large prospective cohort recruited 15,737 healthy men and women across Scotland between 1984 and 1995, and Efficacy of lipoprotein(a) apheresis in followed them through 2009 for CAD and PAD diagnoses. patients with peripheral arterial disease The 20-year risk for PAD hospitalization and mortality was significantly determined by baseline lipoprotein(a) levels with an hazard ratio of 1.21. In contrast, baseline lipopro- A causal relationship between elevated lipoprotein(a) lev- tein(a) levels were not significantly predictive for CAD risk els and PAD that is strongly suggested by prospective in this cohort. cohort studies will finally be proven after lipoprotein(a) The above mentioned findings although apply to popu- lowering therapies have shown to reduce the incidence lations from other geographic origin, as baseline lipopro- and progression of PAD and other cardiovascular events tein(a) levels were also predictive for incident PAD during in PAD patients. There is no effective pharmacological 6-year follow-up in a sample of more than 1000 Italian treatment to lower lipoprotein(a) levels clinically avail- subjects over the age of 60 [17]. able at the moment, although RNA-targeted therapeutics Taken together the above mentioned data strongly sug- to reduce lipoprotein(a) levels already have successfully gest that elevated lipoprotein(a) levels increase the risk of completed phase II clinical trials [19]. Lipoprotein aphere- developing clinical relevant PAD that leads to hospitaliza- sis remains the only treatment option for patients with tion and mortality. Elevated lipoprotein(a) levels seem to be elevated lipoprotein(a) and progressive cardiovascular dis- a more important risk factor for PAD compared with CAD ease despite optimal medical treatment of all conventional (or stroke, the latter data not shown). cardiovascular risk factors. Lipoprotein apheresis has been shown to reduce the rate of cardiovascular events in pa- tients with established coronary artery disease associated with high lipoprotein(a) levels [20–23]. Published data on the efficacy of lipoprotein apheresis in patients with PAD and elevated lipoprotein(a) are sparse, although PAD is highly prevalent in patients that are treated by lipoprotein(a) apheresis. Among 90 patients who started K 42 N. Weiss, U. Julius lipoprotein apheresis due to progressive cardiovascular dis- apheresis also led to a rapid and sustained improvement of ease and either isolated elevated lipoprotein(a) levels or PAD symptoms in all patients. This is indicated by a sig- a combination of elevated lipoprotein(a) and low-density nificant reduction of the pain level from 7.0 ± 1.5 points at lipoprotein cholesterol levels between 2008 and 2013 pe- baseline to 1.6 ± 0.7 after one and 1.1 ± 0.4 after two years ripheral arterial disease was present in 44 and 53% of pa- of lipoprotein apheresis. Consistently, the mean walking tients, respectively [24]. Among the 170 patients in the distance increased from 87 ± 60 m at baseline gradually to “Prospective Lipoprotein(a) Apheresis Registry Pro(a)Life” 402 ± 119 after two years. This went along with a significant that represented around 60% of the German patients that increase in the resting ankle-brachial index in the affected were treated by lipoprotein(a) apheresis in 2011 [21]30 leg. lower limb peripheral arterial events had occurred in the Taken together these data show that lipoprotein aphere- two years before initiation of lipoprotein apheresis. sis rapidly and significantly improves symptoms of PAD The latter registry followed these 170 patients and com- such as pain during physical activity and the walking dis- pared the cardiovascular event rates before and after ini- tance and reduces the rate of clinically driven peripheral tiation of lipoprotein(a) apheresis. In addition to a signifi- revascularizations. cant reduction of major cardiovascular events including my- ocardial infarction, percutaneous coronary intervention and Conclusions coronary artery bypass grafting from 144 in the two years before to 31 in the two years after initiation of lipoprotein apheresis the rate of peripheral arterial events including Elevated lipoprotein(a) levels have been shown to be a risk peripheral arterial angioplasty, stenting or bypass surgery factor for the development of cardiovascular disease in the was reduced from 30 to 11, respectively. Furthermore, other coronary and cerebrovascular circulation. Although ran- non-coronary interventions such as carotid artery stenting domized controlled trials are missing and won’t be possible or surgery or renal artery angioplasty or stenting was re- to perform due to ethical reasons within the near future duced from 7 to 1, respectively [21]. longitudinal observational studies strongly suggest that the In a monocentric, retrospective, longitudinal cohort reduction of lipoprotein(a) levels by lipoprotein apheresis study 35 patients with isolated lipoprotein(a) elevation had significantly and clinical relevantly reduces the incidence been included, and the rate of cardiovascular events in the of cardiovascular events [20–23, 25]. There is increasing 6.8 ± 5.6 years before and 6.8 ± 4.9 years after initiation evidence from case–control studies, cross-sectional cohort of chronic lipoprotein apheresis was compared. Besides studies and longitudinal prospective cohort studies that el- a 90.4% reduction of major adverse cardiac events in- evated lipoprotein(a) levels are a risk factor for the devel- cluding cardiac death, non-lethal myocardial infarction, opment of PAD and for a worse clinical outcome in PAD coronary bypass surgery and percutaneous coronary inter- patients [11–18]. Furthermore, longitudinal observational ventions a reduction of peripheral vascular events from studies indicated that lipoprotein apheresis also reduces the 11 in the years before to 2 in the years after initiation of necessity for clinically driven revascularizations in patients lipoprotein apheresis could be observed [25]. with PAD [21, 23, 25–27]. Whether or not it also reduces Poller and coworkers [26, 27] prospectively followed the extremely high burden of overall cardiovascular morbid- 10 patients who were treated by lipoprotein apheresis due ity and mortality in PAD patients that is higher compared to symptomatic PAD that required a revascularization pro- with patients with isolated CAD [8, 9] has not been studied cedure, had elevated lipoprotein(a) levels above 60 mg/dL so far but seems to be biologically plausible. and were on sufficient treatment of all other cardiovascular Therefore it is good clinical practice that patients with risk factors. Outcome measures were the rate of clinically PAD and progressive disease despite control of all conven- driven revascularizations in the 12 months prior compared tional risk factors should be screened for elevated lipopro- with the 24 months after initiation of lipoprotein apheresis tein(a) levels. In addition patients with elevated lipopro- as well as the ankle-brachial blood pressure index, the walk- tein(a) levels and coronary or cerebrovascular atherosclero- ing distance determined by a standardized treadmill test, as sis should also be screened for the presence of PAD, either well as subjective grading of the mean pain level during symptomatic or asymptomatic, as patients with polyvascu- everyday physical activity on a 10-point visual analogue lar disease in the coronary and peripheral circulation are at scale (the higher the score the worse the pain). Consis- higher risk compared to patients with isolated CAD [10]. tent with the above mentioned study, the study also showed PAD patients with elevated lipoprotein(a) levels and pro- a significant reduction of clinical driven revascularizations gressive disease as indicated by recurrent clinical events re- from 35 procedures during 120 patient–months in the year quiring revascularization or progression of the disease stage before to 2 procedures per 229 patient–months in the two from asymptomatic to intermittent claudication or critical years after initiation of lipoprotein apheresis. Lipoprotein limb ischemia or from intermittent claudication to critical K Lipoprotein(a) apheresis in patients with peripheral arterial disease: rationale and clinical results 43 3. 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Clinical Research in Cardiology SupplementsSpringer Journals

Published: Mar 15, 2019

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