Comment
do not seem to be substantial (table). Because all guidelines recommend prompt initiation of drug treatment in patients with hypertension stage II or III, estimates of total cardiovascular risk in this setting might not have a major effect on therapeutic decisions, but rather on the expectations of benefit. In patients with hypertension stage I, with the notable exception of the Joint National Committee 8, the other guidelines take cardiovascular risk estimates into some account, by recommending the initiation of drug treatment when the risk is increased generally on the basis of target organ damage or established cardiovascular disease. Future studies should focus on stage I hypertension and clarify what is the most accurate and cost-effective approach to stratify cardiovascular risk and to estimate the expected benefit of treatment in these patients. *Paolo Verdecchia, Gianpaolo Reboldi Department of Medicine, Hospital of Assisi, 06081 Assisi, Italy (PV); and Department of Medicine, University of Perugia, Perugia, Italy (GR) [email protected] We declare no competing interests. 1
The Blood Pressure Lowering Treatment Trialists’ Collaboration. Blood pressure-lowering treatment based on cardiovascular risk: a meta-analysis of individual patient data. Lancet 2014; 384: 591–98.
2
3
4
5
6
7 8
9 10
11
12
Cholesterol Treatment Trialists’ (CTT) Collaborators. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 2012; 380: 581–90. Krause T, Lovibond K, Caulfield M, McCormack T, Williams B. Management of hypertension: summary of NICE guidance. BMJ 2011; 343: d4891. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014; 311: 507–20. Hackam DG, Quinn RR, Ravani P, et al. The 2013 Canadian Hypertension Education Program recommendations for blood pressure measurement, diagnosis, assessment of risk, prevention, and treatment of hypertension. Can J Cardiol 2013; 29: 528–42. Ahmed I, Debray TP, Moons KG, Riley RD. Developing and validating risk prediction models in an individual participant data meta-analysis. BMC Med Res Methodol 2014; 14: 3. Altman DG, Royston P. What do we mean by validating a prognostic model? Stat Med 2000; 19: 453–73. Staessen JA, Fagard R, Thijs L, et al, for the Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet 1997; 350: 757–64. Beckett NS, Peters R, Fletcher AE, et al. Treatment of hypertension in patients 80 years of age or older. N Engl J Med 2008; 358: 1887–98. Pitt B. ACE inhibitors for patients with vascular disease without left ventricular dysfunction—may they rest in PEACE? N Engl J Med 2004; 351: 2115–17. Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J 2013; 34: 2159–219. Weber MA, Schiffrin EL, White WB, et al. Clinical practice guidelines for the management of hypertension in the community: a statement by the American Society of Hypertension and the International Society of Hypertension. J Clin Hypertens (Greenwich) 2014; 16: 14–26.
Heparin monotherapy for percutaneous coronary intervention? See Articles page 599
564
The efficacy and safety of percutaneous coronary intervention (PCI) has been substantially enhanced by refinements in antithrombotic treatments. Ischaemic complications were reduced by as much as 50% with addition of platelet glycoprotein IIb/IIIa inhibitors (GPIs) to early regimens of aspirin and heparin.1,2 However, use of these potent platelet inhibitors was accompanied by increased risk of haemorrhagic complications, which are associated with increased mortality, morbidity, and costs.3,4 Development of antithrombotic drugs therefore focused on reducing risks of haemorrhagic events while maintaining protection against ischaemic complications. In several trials in patients undergoing PCI, substitution of the direct thrombin inhibitor bivalirudin for the combination of heparin and a GPI consistently reduced the incidence of major bleeding by about 40%.5–7
Although occurrence of the composite ischaemic endpoints of those trials was not significantly increased by bivalirudin, there seemed to be more frequent periprocedural myocardial infarctions in several studies and rates of acute stent thrombosis were significantly higher with bivalirudin than with heparin in patients with ST-elevation myocardial infarction (STEMI). However, long-term mortality was not increased with bivalirudin and this drug largely supplanted the combination of heparin plus a GPI during PCI. Advances in interventional practices have the potential to alter the balance between bleeding and ischaemic risks. Ticagrelor and prasugrel— potent and rapidly acting inhibitors of the platelet ADP receptor—reduce ischaemic events when used instead of clopidogrel in patients with acute www.thelancet.com Vol 384 August 16, 2014
coronary syndromes.8,9 Although no trial has explicitly tested whether these drugs remove the need for use of a GPI with heparin, GPI use has nonetheless decreased. Radial, rather than femoral, arterial access is becoming more common during PCI, thus reducing the risk of vascular-site haemorrhage and the need for pharmacological measures to control bleeding.10 Newer stent designs with thinner metallic struts eluting second-generation antiproliferative drugs seem to be associated with lower rates of stent thrombosis.11 With changing interventional treatments, recent trials have re-examined bivalirudin compared with heparin-based regimens. Some of these trials took the position that routine GPI use is no longer needed during contemporary PCI, comparing bivalirudin instead with heparin monotherapy (with GPIs used in either group only provisionally for ischaemic complications). In a large trial of this design among patients with STEMI,12 bivalirudin did not reduce bleeding complications and was associated with higher rates of stent thrombosis, myocardial reinfarction, and repeat revascularisation compared with heparin. In The Lancet, Matthew Cavender and Marc Sabatine13 shed some light on seemingly disparate results with bivalirudin in a meta-analysis of randomised trials of bivalirudin versus heparin regimens during coronary stenting. They included 16 trials of nearly 34 000 patients with STEMI (n=4), non-ST-segmentelevation acute coronary syndromes (n=3), or urgent or elective PCI (n=9). They appropriately stratified the trials according to the strategy for use of GPIs: bivalirudin monotherapy versus heparin plus planned GPI (n=9), bivalirudin monotherapy versus heparin monotherapy (n=5), or bivalirudin versus heparin with planned GPI in both groups (n=4). Ischaemic complications of PCI were more frequent among patients assigned to receive bivalirudin-based regimens compared with heparin-based regimens (risk ratio [RR] 1·09, 95% CI 1·01–1·17; p=0·0204), a finding that was consistent regardless of the clinical indication for PCI or the strategy for use of GPIs. However, the effect of bivalirudin on bleeding risk was significantly affected by the strategy for concomitant GPI use. In trials in which GPIs were used routinely with heparin, bleeding was reduced by bivalirudin (RR 0·53, 95% CI 0·47–0·61). In trials comparing bivalirudin with heparin monotherapy, www.thelancet.com Vol 384 August 16, 2014
Science Photo Library
Comment
there was no significant difference in bleeding rates (RR 0·78, 95% CI 0·51–1·19); the single sizeable trial of that design to show reduced haemorrhage risk with bivalirudin (ISAR-REACT 3) used a heparin dose (140 U/kg bodyweight) that was much higher than that used in interventional practice (50–70 U/kg). Findings from this meta-analysis13 suggest that routine use of bivalirudin offers little advantage over heparin among patients undergoing PCI, at least in settings in which ticagrelor or prasugrel are frequently used and vascular access is primarily through the radial artery. The reduction in haemorrhagic events noted with bivalirudin in earlier trials seems to have been due primarily to sparing of the use of GPIs, and cannot be expected when compared with heparin monotherapy. Moreover, rates of myocardial infarction, revascularisation, and stent thrombosis were reduced by heparin versus bivalirudin, independently of concomitant GPI use. However, the comparison between bivalirudin and heparin monotherapy was driven primarily by the results of two large studies: a UK single-centre study12 and a Chinese trial that has not yet been published in a peer-reviewed journal. Moreover, these two trials enrolled patients with STEMI and might not be representative of outcome in settings where ticagrelor and prasugrel are not indicated. Definitive and broader conclusions regarding the efficacy of bivalirudin versus heparin must therefore await results of the multicentre 6800-patient MATRIX trial, which is expected to be completed by the end of 2014 (NCT01433627). 565
Comment
Sometimes old and inexpensive drugs are nevertheless good drugs, and sometimes improvements in medical practice can reinvigorate old drugs. Despite its mechanistic disadvantages, this might be the case with heparin. Unless new trial data to the contrary with bivalirudin become available, the findings of this meta-analysis13 provide a rationale to consider heparin monotherapy as the preferred anticoagulant regimen for contemporary PCI.
4
A Michael Lincoff
9
Cleveland Clinic Coordinating Center for Clinical Research (C5Research), Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA [email protected]
10
I have received grants from Lilly, AstraZeneca, CSL, Roche, Genentech, Regado, Pfizer, Takeda, and Vivus. 1
2
3
EPISTENT Investigators. Randomised placebo-controlled and balloon-angioplasty-controlled trial to assess safety of coronary stenting with use of platelet glycoprotein-IIb/IIIa blockade. Lancet 1998; 352: 87–92. ESPRIT investigators. Novel dosing regimen of eptifibatide in planned coronary stent implantation (ESPRIT): a randomised, placebo-controlled trial. Lancet 2000; 356: 2037–44. Giugliano RP, White JA, Bode C, et al. Early versus delayed, provisional eptifibatide in acute coronary syndromes. N Engl J Med 2009; 360: 2176–90.
5
6 7 8
11 12
13
Rao SV, Kaul PR, Liao L, et al. Association between bleeding, blood transfusion, and costs among patients with non-ST-segment elevation acute coronary syndromes. Am Heart J 2008; 155: 369–74. Lincoff AM, Bittl JA, Harrington RA, et al. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention. The REPLACE-2 trial. JAMA 2003; 289: 853–63. Stone G, McLaurin BT, Cox DA, et al. Bivalirudin for patients with acute coronary syndromes. N Engl J Med 2006; 355: 2203–16. Stone G, Witzenbichler B, Guagliumi G, et al. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008; 358: 2218–30. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361: 1045–57. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357: 2001–15. Romagnoli E, Biondi-Zoccai G, Sciahbasi A, et al. Radial versus femoral randomized investigation in ST-segment elevation acute coronary syndrome. J Am Coll Cardiol 2012; 60: 2481–89. Palmerini T, Biondi-Zoccai G, Della Riva D, et al. Stent thrombosis with drug-eluting stents. J Am Coll Cardiol 2013; 62: 1915–21. Shahzad A, Kemp I, Mars C, et al. Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention (HEAT-PPCI): an open-label, single centre, randomised controlled trial. Lancet 2014; published online July 4. http://dx.doi.org/10.1016/S01406736(14)60924-7. Cavender MA, Sabatine MS. Bivalirudin versus heparin in patients planned for percutaneous coronary intervention: a meta-analysis of randomised controlled trials. Lancet 2014; 384: 599–606.
Dyslipidaemia in perspective See Series pages 607, 618, and 626
566
Dyslipidaemia as the original cause of atherosclerotic vascular disease has returned to centre stage, 20 years after the results of the 4S study1 were published in The Lancet in 1994. The 4S study heralded the beginning of the great success of statins, now the most widely prescribed class of drugs in the history of medicine. The three Series papers in this issue of The Lancet on the consequences of perturbed lipoprotein metabolism for vascular disease are an education on their own.2–4 The authors provide balanced and thorough overviews on what is known and, most importantly, still unknown in the specialty. LDL cholesterol2 has been at the core of atherogenesis for so long in our collective memory that few clinicians have any doubt about its causal role in heart disease. Most clinicians regard familial hypercholesterolaemia to be the best example of that association, and are convinced by the Oxford meta-analysis showing that statins exert their beneficial effects through lowering of LDL cholesterol concentrations.5,6 The massive power of the large lipid genetics consortia and their mendelian randomisation approach in dyslipidaemia have further
cemented the role of LDL cholesterol as a cause of atherosclerotic vascular disease.7 Nevertheless, not every question has been fully answered, including why has it not been shown convincingly with any other class of drugs that reduction of cardiovascular events follows LDL cholesterol lowering as closely as it does with statins. Despite cholestyramine and partial ileal bypass surgery showing reductions in cardiovascular events in the pre-statin era, results of outcome trials are awaited with a cholesterol absorption inhibitor (IMPROVE-IT [NCT00202878]) and a monoclonal antibody targeting PCSK9 (ODYSSEY Outcomes [NCT01663402], FOURIER [NCT01764633], SPIRE I [NCT01975376], and SPIRE II [NCT01975389]), with success defined as results close to the CTT regression line (ie, a relation that would show an association between LDL cholesterol lowering and event reduction). Such findings should convince sceptics and would make investigation of where the association ends possible; this point is unlikely to be at zero, but will probably be well below 25 mg/dL (0·65 mmol/L), the true physiological LDL cholesterol concentration. www.thelancet.com Vol 384 August 16, 2014
do not seem to be substantial (table). Because all guidelines recommend prompt initiation of drug treatment in patients with hypertension stage II or III, estimates of total cardiovascular risk in this setting might not have a major effect on therapeutic decisions, but rather on the expectations of benefit. In patients with hypertension stage I, with the notable exception of the Joint National Committee 8, the other guidelines take cardiovascular risk estimates into some account, by recommending the initiation of drug treatment when the risk is increased generally on the basis of target organ damage or established cardiovascular disease. Future studies should focus on stage I hypertension and clarify what is the most accurate and cost-effective approach to stratify cardiovascular risk and to estimate the expected benefit of treatment in these patients. *Paolo Verdecchia, Gianpaolo Reboldi Department of Medicine, Hospital of Assisi, 06081 Assisi, Italy (PV); and Department of Medicine, University of Perugia, Perugia, Italy (GR) [email protected] We declare no competing interests. 1
The Blood Pressure Lowering Treatment Trialists’ Collaboration. Blood pressure-lowering treatment based on cardiovascular risk: a meta-analysis of individual patient data. Lancet 2014; 384: 591–98.
2
3
4
5
6
7 8
9 10
11
12
Cholesterol Treatment Trialists’ (CTT) Collaborators. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 2012; 380: 581–90. Krause T, Lovibond K, Caulfield M, McCormack T, Williams B. Management of hypertension: summary of NICE guidance. BMJ 2011; 343: d4891. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014; 311: 507–20. Hackam DG, Quinn RR, Ravani P, et al. The 2013 Canadian Hypertension Education Program recommendations for blood pressure measurement, diagnosis, assessment of risk, prevention, and treatment of hypertension. Can J Cardiol 2013; 29: 528–42. Ahmed I, Debray TP, Moons KG, Riley RD. Developing and validating risk prediction models in an individual participant data meta-analysis. BMC Med Res Methodol 2014; 14: 3. Altman DG, Royston P. What do we mean by validating a prognostic model? Stat Med 2000; 19: 453–73. Staessen JA, Fagard R, Thijs L, et al, for the Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet 1997; 350: 757–64. Beckett NS, Peters R, Fletcher AE, et al. Treatment of hypertension in patients 80 years of age or older. N Engl J Med 2008; 358: 1887–98. Pitt B. ACE inhibitors for patients with vascular disease without left ventricular dysfunction—may they rest in PEACE? N Engl J Med 2004; 351: 2115–17. Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J 2013; 34: 2159–219. Weber MA, Schiffrin EL, White WB, et al. Clinical practice guidelines for the management of hypertension in the community: a statement by the American Society of Hypertension and the International Society of Hypertension. J Clin Hypertens (Greenwich) 2014; 16: 14–26.
Heparin monotherapy for percutaneous coronary intervention? See Articles page 599
564
The efficacy and safety of percutaneous coronary intervention (PCI) has been substantially enhanced by refinements in antithrombotic treatments. Ischaemic complications were reduced by as much as 50% with addition of platelet glycoprotein IIb/IIIa inhibitors (GPIs) to early regimens of aspirin and heparin.1,2 However, use of these potent platelet inhibitors was accompanied by increased risk of haemorrhagic complications, which are associated with increased mortality, morbidity, and costs.3,4 Development of antithrombotic drugs therefore focused on reducing risks of haemorrhagic events while maintaining protection against ischaemic complications. In several trials in patients undergoing PCI, substitution of the direct thrombin inhibitor bivalirudin for the combination of heparin and a GPI consistently reduced the incidence of major bleeding by about 40%.5–7
Although occurrence of the composite ischaemic endpoints of those trials was not significantly increased by bivalirudin, there seemed to be more frequent periprocedural myocardial infarctions in several studies and rates of acute stent thrombosis were significantly higher with bivalirudin than with heparin in patients with ST-elevation myocardial infarction (STEMI). However, long-term mortality was not increased with bivalirudin and this drug largely supplanted the combination of heparin plus a GPI during PCI. Advances in interventional practices have the potential to alter the balance between bleeding and ischaemic risks. Ticagrelor and prasugrel— potent and rapidly acting inhibitors of the platelet ADP receptor—reduce ischaemic events when used instead of clopidogrel in patients with acute www.thelancet.com Vol 384 August 16, 2014
coronary syndromes.8,9 Although no trial has explicitly tested whether these drugs remove the need for use of a GPI with heparin, GPI use has nonetheless decreased. Radial, rather than femoral, arterial access is becoming more common during PCI, thus reducing the risk of vascular-site haemorrhage and the need for pharmacological measures to control bleeding.10 Newer stent designs with thinner metallic struts eluting second-generation antiproliferative drugs seem to be associated with lower rates of stent thrombosis.11 With changing interventional treatments, recent trials have re-examined bivalirudin compared with heparin-based regimens. Some of these trials took the position that routine GPI use is no longer needed during contemporary PCI, comparing bivalirudin instead with heparin monotherapy (with GPIs used in either group only provisionally for ischaemic complications). In a large trial of this design among patients with STEMI,12 bivalirudin did not reduce bleeding complications and was associated with higher rates of stent thrombosis, myocardial reinfarction, and repeat revascularisation compared with heparin. In The Lancet, Matthew Cavender and Marc Sabatine13 shed some light on seemingly disparate results with bivalirudin in a meta-analysis of randomised trials of bivalirudin versus heparin regimens during coronary stenting. They included 16 trials of nearly 34 000 patients with STEMI (n=4), non-ST-segmentelevation acute coronary syndromes (n=3), or urgent or elective PCI (n=9). They appropriately stratified the trials according to the strategy for use of GPIs: bivalirudin monotherapy versus heparin plus planned GPI (n=9), bivalirudin monotherapy versus heparin monotherapy (n=5), or bivalirudin versus heparin with planned GPI in both groups (n=4). Ischaemic complications of PCI were more frequent among patients assigned to receive bivalirudin-based regimens compared with heparin-based regimens (risk ratio [RR] 1·09, 95% CI 1·01–1·17; p=0·0204), a finding that was consistent regardless of the clinical indication for PCI or the strategy for use of GPIs. However, the effect of bivalirudin on bleeding risk was significantly affected by the strategy for concomitant GPI use. In trials in which GPIs were used routinely with heparin, bleeding was reduced by bivalirudin (RR 0·53, 95% CI 0·47–0·61). In trials comparing bivalirudin with heparin monotherapy, www.thelancet.com Vol 384 August 16, 2014
Science Photo Library
Comment
there was no significant difference in bleeding rates (RR 0·78, 95% CI 0·51–1·19); the single sizeable trial of that design to show reduced haemorrhage risk with bivalirudin (ISAR-REACT 3) used a heparin dose (140 U/kg bodyweight) that was much higher than that used in interventional practice (50–70 U/kg). Findings from this meta-analysis13 suggest that routine use of bivalirudin offers little advantage over heparin among patients undergoing PCI, at least in settings in which ticagrelor or prasugrel are frequently used and vascular access is primarily through the radial artery. The reduction in haemorrhagic events noted with bivalirudin in earlier trials seems to have been due primarily to sparing of the use of GPIs, and cannot be expected when compared with heparin monotherapy. Moreover, rates of myocardial infarction, revascularisation, and stent thrombosis were reduced by heparin versus bivalirudin, independently of concomitant GPI use. However, the comparison between bivalirudin and heparin monotherapy was driven primarily by the results of two large studies: a UK single-centre study12 and a Chinese trial that has not yet been published in a peer-reviewed journal. Moreover, these two trials enrolled patients with STEMI and might not be representative of outcome in settings where ticagrelor and prasugrel are not indicated. Definitive and broader conclusions regarding the efficacy of bivalirudin versus heparin must therefore await results of the multicentre 6800-patient MATRIX trial, which is expected to be completed by the end of 2014 (NCT01433627). 565
Comment
Sometimes old and inexpensive drugs are nevertheless good drugs, and sometimes improvements in medical practice can reinvigorate old drugs. Despite its mechanistic disadvantages, this might be the case with heparin. Unless new trial data to the contrary with bivalirudin become available, the findings of this meta-analysis13 provide a rationale to consider heparin monotherapy as the preferred anticoagulant regimen for contemporary PCI.
4
A Michael Lincoff
9
Cleveland Clinic Coordinating Center for Clinical Research (C5Research), Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA [email protected]
10
I have received grants from Lilly, AstraZeneca, CSL, Roche, Genentech, Regado, Pfizer, Takeda, and Vivus. 1
2
3
EPISTENT Investigators. Randomised placebo-controlled and balloon-angioplasty-controlled trial to assess safety of coronary stenting with use of platelet glycoprotein-IIb/IIIa blockade. Lancet 1998; 352: 87–92. ESPRIT investigators. Novel dosing regimen of eptifibatide in planned coronary stent implantation (ESPRIT): a randomised, placebo-controlled trial. Lancet 2000; 356: 2037–44. Giugliano RP, White JA, Bode C, et al. Early versus delayed, provisional eptifibatide in acute coronary syndromes. N Engl J Med 2009; 360: 2176–90.
5
6 7 8
11 12
13
Rao SV, Kaul PR, Liao L, et al. Association between bleeding, blood transfusion, and costs among patients with non-ST-segment elevation acute coronary syndromes. Am Heart J 2008; 155: 369–74. Lincoff AM, Bittl JA, Harrington RA, et al. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention. The REPLACE-2 trial. JAMA 2003; 289: 853–63. Stone G, McLaurin BT, Cox DA, et al. Bivalirudin for patients with acute coronary syndromes. N Engl J Med 2006; 355: 2203–16. Stone G, Witzenbichler B, Guagliumi G, et al. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008; 358: 2218–30. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361: 1045–57. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357: 2001–15. Romagnoli E, Biondi-Zoccai G, Sciahbasi A, et al. Radial versus femoral randomized investigation in ST-segment elevation acute coronary syndrome. J Am Coll Cardiol 2012; 60: 2481–89. Palmerini T, Biondi-Zoccai G, Della Riva D, et al. Stent thrombosis with drug-eluting stents. J Am Coll Cardiol 2013; 62: 1915–21. Shahzad A, Kemp I, Mars C, et al. Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention (HEAT-PPCI): an open-label, single centre, randomised controlled trial. Lancet 2014; published online July 4. http://dx.doi.org/10.1016/S01406736(14)60924-7. Cavender MA, Sabatine MS. Bivalirudin versus heparin in patients planned for percutaneous coronary intervention: a meta-analysis of randomised controlled trials. Lancet 2014; 384: 599–606.
Dyslipidaemia in perspective See Series pages 607, 618, and 626
566
Dyslipidaemia as the original cause of atherosclerotic vascular disease has returned to centre stage, 20 years after the results of the 4S study1 were published in The Lancet in 1994. The 4S study heralded the beginning of the great success of statins, now the most widely prescribed class of drugs in the history of medicine. The three Series papers in this issue of The Lancet on the consequences of perturbed lipoprotein metabolism for vascular disease are an education on their own.2–4 The authors provide balanced and thorough overviews on what is known and, most importantly, still unknown in the specialty. LDL cholesterol2 has been at the core of atherogenesis for so long in our collective memory that few clinicians have any doubt about its causal role in heart disease. Most clinicians regard familial hypercholesterolaemia to be the best example of that association, and are convinced by the Oxford meta-analysis showing that statins exert their beneficial effects through lowering of LDL cholesterol concentrations.5,6 The massive power of the large lipid genetics consortia and their mendelian randomisation approach in dyslipidaemia have further
cemented the role of LDL cholesterol as a cause of atherosclerotic vascular disease.7 Nevertheless, not every question has been fully answered, including why has it not been shown convincingly with any other class of drugs that reduction of cardiovascular events follows LDL cholesterol lowering as closely as it does with statins. Despite cholestyramine and partial ileal bypass surgery showing reductions in cardiovascular events in the pre-statin era, results of outcome trials are awaited with a cholesterol absorption inhibitor (IMPROVE-IT [NCT00202878]) and a monoclonal antibody targeting PCSK9 (ODYSSEY Outcomes [NCT01663402], FOURIER [NCT01764633], SPIRE I [NCT01975376], and SPIRE II [NCT01975389]), with success defined as results close to the CTT regression line (ie, a relation that would show an association between LDL cholesterol lowering and event reduction). Such findings should convince sceptics and would make investigation of where the association ends possible; this point is unlikely to be at zero, but will probably be well below 25 mg/dL (0·65 mmol/L), the true physiological LDL cholesterol concentration. www.thelancet.com Vol 384 August 16, 2014
