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The future of interventional cardiology
THE LANCET
INTERVENTIONAL CARDIOLOGY
The future of interventional cardiology Laura A Corr In less than 20 years the face of cardiology has changed. A new subspecialty of "interventional cardiology" has developed which is part medical and part surgical, and covers all the technical procedures used to treat cardiac diseases without conventional surgery. These include mitral and pulmonary valvotomies and several paediatric procedures such as closure of a patent ductus arteriosus or atrial septal defect, but by far the most common procedure is percutaneous transluminal coronary angioplasty (PTCA). The subspecialty can be traced to the day in 1929 when Forssmann showed he could place a catheter in his own heart and survive. M a n y years later, Sones, a paediatrician, accidentally injected contrast medium into the coronary tree and obtained the first coronary arteriogram. The fact that the large volume of contrast medium caused an episode of ventricular fibrillation did not discourage him from pursuing the observation and paving the way for the era of diagnostic angiography. But interventional cardiology began with Andreas Gruentzig, a young Swiss physician, who was impressed by Dotter's technique of peripheral artery dilation with rigid dilators. Working initially on his kitchen table, he developed the first balloon catheters small enough to reach into the coronary arteries. In 1977 he performed the first successful coronary artery dilation; by the millenium the rate of angioplasty worldwide will easily exceed one million per year.
associated with P T C A approach those of coronary artery bypass grafting (CABG) over a period of three years, 3 and to date the benefits accruing from coronary interventions in this group appear modest, so the cost-benefit analysis of this larger trial is likely to be unfavourable. Whether the economic drawback would slow the exponential rise in the use of angioplasty remains to be seen.
Immediate angioplasty for acute coronary syndromes Angioplasty is invaluable in patients with unstable angina who do not settle on medical therapy, often allowing rapid and complete resolution of the symptoms and early discharge from hospital. 4 In the setting of acute myocardial infarction, several small studies suggested that immediate angioplasty established reperfusion more quickly and more effectively than thrombolysis and was associated with a lower mortality2 The financial implications of this strategy are prohibitive--fully staffed interventional catheter laboratories available 24 hours a day in every district general hospital--and those responsible for the provision of health care are probably relieved to note the preliminary results of the large G U S T O II trial, which just failed to show a significant benefit for angioplasty over thrombolysis when the practice was extended outside the high-volume established interventional centres. Nonetheless, there is still a strong drive amongst trained cardiologists to introduce the policy of immediate angioplasty, particularly for young patients with large anterior infarcts.
A triumph of practice over theory Angioplasty should not work. The pathology of the atherosclerotic plaque is complex with its macrophageladen, lipid-rich core and fibrous cap that is frequently calcified. Gruentzig believed that angioplasty compressed the plaque "like footprints in the snow", but we now know that plaque compression is a minor feature and the principal mechanism of action of angioplasty is to create dissection. Pressures of 6-16 atmospheres are routinely used with the newer balloons to crack the stenoses. The endothelium is disrupted. There is substantial recoil of the dilated vessel and a vigorous migration of smooth muscle cells in response to the injury causes more than 50% restenosis in a quarter to half the vessels dilated. It is astonishing that such a crude technique actually produces clinical benefit, but P T C A is widely use d in patients with chronic stable angina and unstable angina and increasingly in acute myocardial infarction.
The role of PTCA Angioplasty versus medical therapy Many interventions are conducted in patients who would formerly have been managed on medical therapy. Two small trials have examined the benefit of P T C A in patients with chronic stable angina. In one there was a modest but significant reduction in ischaemia and improvement in wellbeing, but neither trial was of a size to detect any difference in the rate of acute myocardial infarction or death? '2 Belatedly, a larger randomised controlled trial (RITA II) to examine this question with modern angioplasty techniques is now underway. The costs
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Will angioplasty replace coronary artery bypass grafting? Much work has been done to compare the benefits of P T C A and CABG. The results of several major trials with follow-up over 1-5 years show remarkably consistent results6'7: there was no difference in the rate of death or myocardial infarction but patients were much more likely to need a subsequent procedure in the first year after P T C A and were less likely to be free of angina. Recovery was quicker after P T C A but long-term return to work was no different. The differences between the two techniques tended to diminish over time. Similarly, the benefit of lower costs associated with the initial P T C A procedure compared with CABG fell over time because of the costs of the further revascularisation procedures required. A meta-analysis of 3371 patients followed up over 2'7 years showed that 4-6% of patients undergoing P T C A and 4"4% of patients undergoing CABG died during follow-up. The combined rate of cardiac death or non-fatal myocardial infarction was 9'9% and 9"3%, respectively. 34% of P T C A patients needed a further revascularisation procedure, including 18% who subsequently undel~vent CABG. 6 The implications of these trial results for the future of interventional cardiology versus bypass surgery have been fiercely debated. Those who favour CABG point out that the trial patients were highly selected: patients with left main stem disease and many with three-vessel disease and impaired left ventricular function, for whom surgery would be expected to improve prognosis, were not
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randomised. The role of angioplasty in such patients is unknown. Even in the low-risk group who were randomised, P T C A was no safer than surgery--largely on account of uncontrolled vessel dissection. For relief of symptoms, surgery undoubtedly provided a more reliable short-term result because of the problem of restenosis after angioplasty. Conversely, those who favour P T C A point out that the short-term follow-up emphasises the problem of restenosis, which occurs within the first six months, whereas the failure rate of saphenous vein bypass grafts rises sharply only after 5-8 years. Re-do surgery carries higher risks than the first operation while re-do P T C A is no more hazardous than the primary procedure and 80% of patients in the trials were successfully managed by angioplasty alone2 These arguments largely miss the point. In clinical practice, both techniques have advantages and disadvantages and direct comparison of the two is probably inappropriate. Technical considerations based on the patter~a of disease (eg, discrete lesions versus diffuse disease, vessel tortuosity, and calcification) or the circumstances of a particular patient (age, concomitant disease) will determine the likelihood of one technique being favoured over the other in the short term. Neither mode of treatment cures the underlying disease and longterm treatment strategies will use both interventions in a complementary fashion. Furthermore, both angioplasty and surgical techniques are changing. The introduction of stenting (see below) has altered the safety and long-term efficacy of P T C A to such an extent that many of the current data on angioplasty are obsolete. Similarly, the use of limited thoracotomies for internal mammary artery grafting to the left anterior descending artery, while regarded by some as a gimmick, may yet allow the prognostic benefits of surgery to be gained without the drawbacks of sternotomies, leg wounds, and cardiopulmonary bypass. 8 The complementary role of this minimally invasive surgery and invasive cardiology is evident.
Overcoming the limitations of angioplasty Drugs and devices The angioplasty trials emphasised the limitations of the technique of simple balloon dilation--the appreciable acute complication rate due to uncontrolled vessel dissection and, more importantly, the huge clinical and economic costs of restenosis. Many years and many millions of dollars were spent searching for the solution. Basic science laboratories throughout the world developed animal models of restenosis and thousands of compounds were tested in vitro and in vivo. But despite the enthusiasm and dedication of the scientists, not one of the compounds shown to be effective in animals was effective in clinical practice. Hypotheses about the reasons for this include the differences between human atherosclerosis and the animal models, the method of delivery, and simply the concentrations of the compounds required. Meanwhile interventionists were trying new techniques aimed at debulking the plaque burden in the hope of reducing acute complications and the stimulus to restenosis. Devices such as directional coronary atherectomy became quite widely used before the large randomised CAVEAT and C C A T trials demonstrated no clinical benefit. 9'~°The use of laser energy in various forms to ablate atheromatous plaque initially attracted much excitement bu~ registry data suggested an unacceptably s24
THE LANCET
increased rate of restenosis and a recent randomised trial has also shown no benefit over plain balloon angioplasty. H Many bulky and expensive machines are now sitting forlorn and unused in the corner of catheter laboratories around the world. High-speed rotational ablation with a diamond-studded burr is said to have a niche in thin calcified vessels (which are notoriously difficult to treat by angioplasty), but again randomised trial data are lacking. Enthusiasm for such devices is waning.
The era of stenting Stents deserve to be awarded a category of their own. These small metallic mesh tubes can be crimped onto angioplasty balloons and inflated across a stenosis, embedding themselves permanently into the vessel wall and holding the artery widely open. They are easy to use and were first approved by the US Food and Drug Administration in 1992 for the management of abrupt vessel closure after PTCA. Stents are the ideal adjunct to balloon angioplasty since they seal the dissection and prevent vessel recoil. The result both angiographically and haemodyamically is very attractive. Furthermore, the large randomised B E N E S T E N T (Belgium-Netherlands Stent Study) and STRESS (Stent Restenosis Study) trials with the Palmaz-Schatz stent both showed a reduction in the need for repeated revascularisaton at six months compared with balloon angioplasty (17% vs 25%, p=0.005 in B E N E S T E N T , 10% vs 15%, p=0.06 in STRESS)32'13 This benefit is almost certainly not due to inhibition of smooth muscle proliferation, which may even be aggravated; more likely, the increased vessel lumen allows greater hypertrophy without clinical restenosis. In 1994, the FDA approved the use of the Palmaz-Schatz stent in selected patients to prevent coronary restenosis after angioplasty. The pace of change in interventional cardiology is such that even these trials are now out of date. Initial experience with stents in the late 1980s was complicated by an unacceptably high rate of stent thrombosis, so patients in the trials were treated with aspirin, dipyridamole, dextran, heparin, and warfarin in the days after stenting. Unsurprisingly, these gave rise to high rates of vascular complications at the site of the groin puncture, yet the rate of stent thrombosis remained stubbornly around 5-9%. Since then it has become apparent that stenting can be safely achieved with antiplatelet agents such as aspirin and ticlopidine alone, provided that the stents are adequately deployed24 Intravascular ultrasound has been helpful in identifying optimal expansion although it remains predominantly a research tool. The effect of this simplified regimen has been to produce an explosion in the use of stenting. Thrombosis rates now seem to be less than 1% and patients are increasingly discharged from hospital after one night, with a consequent reduction in hospital costs. '~ Stents have reduced the need for bail-out CABG to such an extent that arguments are being made for angioplasty to be performed in centres without surgical backup. Stenting is now routinely conducted in 25% of angioplasties in Europe with rates as high as 70% in some institutions, and there is no sign of any decline. Unanswered questions
Developments in technology have outpaced scientific study and the dizzying pace of change in interventional cardiology leaves many questions unanswered. Stents were
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INTERVENTIONAL CARDIOLOGY
first p u t into coronary arteries t e n years ago b u t have b e e n u s e d in massive n u m b e r s only in the past two to t h r e e years. T h e i r l o n g - t e r m efficacy and, m o r e i m p o r t a n t l y , safety r e m a i n s to b e seen. S o m e early reports suggest good o u t c o m e s at three years '~ b u t if t h e r e are adverse effects, for example due to the rigidity of the m e t a l t u b e s in the c o n s t a n t l y flexing c o r o n a r y arteries after t e n or t w e n t y years, the c o n s e q u e n c e s c o u l d b e catastrophic. In the more immediate future, the cost-benefit i m p l i c a t i o n s n e e d to b e addressed. A n g i o p l a s t y a n d s t e n t i n g are satisfying to do a n d are p o p u l a r w i t h patients a n d their general physicians alike, b e i n g relatively n o n invasive a n d often p r o d u c i n g a d r a m a t i c if s o m e t i m e s s h o r t - t e r m benefit. T h u s n o - o n e is inclined to resist t h e tide, with t h e exception o f those w h o pay for h e a l t h care w h o m a y b e f o r c e d to d o so b y s i m p l e e c o n o m i c constraints. T h e t e c h n i q u e requires expensive e q u i p m e n t a n d staff a n d hospital admission. T h e only h o p e f u l factor, albeit s o m e w h a t marginal, is t h a t c o m p e t i t i o n in the m a r k e t is intense; balloons already sell at a fraction of t h e i r original price, a n d stents, too, are likely to fall in price.
W h a t does t h e f u t u r e hold? Advances in stenting I n the developed world the incidence of ischaemic h e a r t disease is declining a n d advances in d r u g therapy, s u c h as the use of the statins to lower cholesterol, m a y have f u r t h e r impact; b u t the ageing o f the p o p u l a t i o n m e a n s t h a t i n t e r v e n t i o n a l cardiology is here to stay. T h e r e will u n d o u b t e d l y be d e v e l o p m e n t s in s t e n t design over the next few years: already the original P a l m a z - S c h a t z s t e n t has b e e n challenged by stents t h a t are m o r e flexible w h e n collapsed, provide equally strong support, a n d are m a d e in various lengths. H e p a r i n - c o a t e d stents, d e v e l o p e d d u r i n g t h e era o f aggressive a n t i c o a g u l a t i o n , s e e m to give excellent results, a l t h o u g h it is n o t clear w h e t h e r they are any better than non-coated stents when properly deployed. '~ P o l y m e r stents w h i c h w o u l d b e a b s o r b e d slowly a n d h e n c e obviate any l o n g - t e r m h a z a r d s are a n attractive c o n c e p t b u t do n o t look p r o m i s i n g w i t h c u r r e n t materials. T h e q u e s t i o n of restenosis w i t h i n stents is currently the subject of study. Several o f the devices t h a t f o u n d e r e d in c o m p a r i s o n with balloon angioplasty are b e i n g tried here b u t I suspect this is m o r e in h o p e t h a n in expectation. S o m e p r e l i m i n a r y work w i t h local intravascular irradiation to r e d u c e intimal hyperplasia looks p r o m i s i n g in animals a n d early work is u n d e r w a y in m a n . 17
The contribution of molecular cardiology P r o b a b l y the m o s t exciting d e v e l o p m e n t s will c o m e f r o m m o l e c u l a r cardiology, w h e r e advances have b e e n m a d e in the d e v e l o p m e n t of agents as adjuncts to angioplasty a n d as therapies w h e r e n e i t h e r surgery n o r angioplasty is suitable. I n 1996, two large studies of the glycoprotein IIb/IIIa a n t i b o d y c7E3 F a b (abciximab; R e o P r o ) , w h i c h is a p o w e r f u l a n t i p l a t e l e t a g e n t , were p r e s e n t e d . T h e E P I L O G a n d C A P T U R E trials h a d b e e n p r e m a t u r e l y s t o p p e d in D e c e m b e r , 1995, b y the safety a n d efficacy m o n i t o r i n g c o m m i t t e e after t h e r e c r u i t m e n t o f only 1 0 0 0 - 1 5 0 0 p a t i e n t s b e c a u s e of a h i g h l y s i g n i f i c a n t r e d u c t i o n in d e a t h a n d myocardial infarction in p a t i e n t s u n d e r g o i n g angioplasty b o t h electively a n d for u n s t a b l e a n g i n a . '~ T h i s a n t i b o d y p r e v e n t s t h r o m b o t i c vessel reocclusion a n d m a y prove useful in u n s t a b l e angina,
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t r a n s i e n t c e r e b r a l i s c h a e m i c attacks, a n d m y o c a r d i a l infarction as well as in the p r e v e n t i o n of complications of angioplasty. T h e i m p a c t o n restenosis is n o t yet known. T h e s m o o t h m u s c l e cell p r o l i f e r a t i o n u n d e r l y i n g restenosis is a n attractive target for m o l e c u l a r strategies in view o f our existing k n o w l e d g e of gene-related cellular proliferation. N a b e l a n d h e r co-workers '9 successfully established transfer o f foreign D N A to arterial walls using catheter techniques, and others have demonstrated t h e r a p e u t i c effects in a n i m a l s . T r a n s g e n e e x p r e s s i o n seems to b e transient, lasting only t h r e e weeks or so, b u t this m a y be sufficient for applications such as p r e v e n t i o n of restenosis. I s n e r a n d co-workers 2° lately r e p o r t e d clinical e v i d e n c e of a n g i o g e n e s i s i n a p a t i e n t w i t h severe peripheral ischaemia after arterial angioplasty gene t r a n s f e r of a p l a s m i d t h a t e n c o d e s for vascular endothelial g r o w t h factor. T h e d e v e l o p m e n t of t h r e e spider a n g i o m a s distal to the site of gene transfer is strong, if indirect, evidence of gene expression. T h i s t e c h n i q u e could have exciting implications for m a n y p a t i e n t s with extensive a n d distal disease for w h o m n e i t h e r C A B G n o r angioplasty has m u c h to offer at present.
And n e x t . . . ? F u r t h e r d e v e l o p m e n t of existing t e c h n i q u e s will have only m a r g i n a l impact. T h e large group of patients w h o die s u d d e n l y of a n a c u t e m y o c a r d i a l i n f a r c t i o n w i t h o u t r e a c h i n g hospital m u s t b e t h e next target for cardiologists, if we look for a substantial r e d u c t i o n of mortality from i s c h a e m i c h e a r t disease. M y o c a r d i a l i n f a r c t i o n is frequently related to a vessel s e g m e n t t h a t was n o t severely s t e n o s e d b e f o r e t h e p l a q u e r u p t u r e o c c u r r e d ; lipid l o w e r i n g s e e m s to r e d u c e p l a q u e v u l n e r a b i l i t y to d i s r u p t i o n r a t h e r t h a n p l a q u e size a n d m a y have a n i m p o r t a n t role to play h e r e . F o r the i n t e r v e n t i o n a l cardiologist, t h e task is to l e a r n to identify at-risk plaques, perhaps using intravascular ultrasound or m i c r o t h e r m i s t o r s , z' a n d t h e n to t e s t w h e t h e r early i n t e r v e n t i o n c a n alter the n a t u r a l history of the disease. T h e challenge is formidable.
References 1 Parisi AF, Folland ED, Hartigan P, oll behalf of the Veterans Affairs ACME investigators. A cmnparison of angioplasty with medical therapy in the treatment of single vessel coronary artery disease. N Engl timed 1992; 326: 10-16. 2 SieversB, Hamm C, Herzner AE. Medical therapy versus PTCA: a prospective, randomised trial in patients with asymptomatic coronary single vessel disease. Circulation 1993; 88 (part II): 1-297. 3 Wientraub WS, Maudlin PD, Becket E, Kosinski AS, King SB III. A comparison of the costs of and quality of life after coronary angioplasty or coronary surgery for multivessel coronary arter disease. Results from the Emory Angioplasty versus Sm'gery Trial (EAST). Circulation 1995; 92: 2831-40. BentivoglioLG, Detre K, Yeh W, Williams DO, Kelsey SF, Faxon DP. Outcome of percutaneous transluminat coronary angioplasty in subsets of unstable angina pectoris. A report of the 1985-1986 National Heart, Lung, and Blood Institute Percutaneous Transluminal Coronary Angioplasty Registry. ,yAm Coll Cardio11994; 24:1195-206. O'Neill WW, Zijlstra F, Suryapranata H, Timmis GC, Grines CL. Meta-analysis of the PAMI and Netherlands randomised trials of primary angioplasty versus thrombolytic therapy for acute myocardial infarction. Circulation 1993; 88: 1-106. Pocock St, Henderson RA, Rickards AF, et al. Meta-analysis of randomised trials comparing coronary angioplasty with bypass surgery. Lancet 1995; 346: 1184-89. The Bypass Angioplasty Revascularisation Iaavestigation(BARI) Investigators. Comparison of coronary bypass surgery with angioplasty in patients with multivessel disease. N EngltiMed 1996; 335: 217-25. Calafiore AM, Angelini GD. Left anterior small thoracotomy (LAST) for coronary artery revascularisation. Lancet 1996; 347: 263-6,t.
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Topol EJ, Leya F, Pinkerton CA, et al. A comparison of directional atherectomy with coronary angioplasty in patients with coronary artery disease. N EngIJ Med 1993; 329: 221-27. Adelman AG, Cohen EC, Kimball BP, et ak A comparison of directional atherectomy with balloon angioplasty for lesions of the left anterior descending coronary artery. N EnglJMed 1993; 329: 228-33. Appelman YEA, Pick JJ, Stril~verda S, et al. Randomised trial of excimer laser angioplasty versus balloon angioplasty for treatment of obstructive coronary artery disease. Lancet 1996; 347: 79-84. Serruys PW, de Iaegere P, Kiemeneij F, et al. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. N E n g l J M e d 1994; 331: 489-95. Fischman D, Leon MB, Balm DS, et al. A randomised comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. N EnglJ ivied t994; 331: 496-501. Corr LA. Is anticoagulation for intracoronary stenting justified? Eur HeartJ 1996; 17: 1296. Kimura T, Yokoi H, Nakagawa Y, et al. Three-year follow-up after implantation of metallic coronary-artery stents. N Engl J Med 1996; 334: 561-66.
THE LANCET 16 Serruys PW, Emanuelsson H, van der Giessen W, et al. Heparincoated Pahnaz-Schatz stents in h u m a n coronary arteries. Early outcome of the B E N E S T E N T - I I pilot study. Circulation 1996; 93: 412-22. 17 Tierstein PS, Massullo V, Jani S, et al. A randomised, clinical trial of radiation therapy to reduce restenosis following coronary stenting-early results. J A m Coll Cardiol t996; 27:15A. 18 Van der Werf F. More evidence for a beneficial effect of platelet glycoprotein IIb/IIIa-blockade during coronary interventions. Latest results from the E P I L O G and C A P T U R E trials. EurHeartJ 1996; 17: 325-26. 19 Nabel EJ, Plautz G, Nabel GJ. Site-specific gene expression in vivo by direct gene transfer into the arterial wail. Science 1990; 249: 1285-88. 20 Isner JM, Pieczek A, Schainfeld R~ et al. Clinical evidence of angiogenesis after arterial gene transfer o f p h V E G F 1 6 5 in patient with ischaemic limb. Lancet 1996; 348: 370-74. 21 Casscells W, Hathorn B, David M, et al. Thermal detection of ceUular infiltrates in living atherosclerotic plaques: possible implications for plaque rupture and thrombosis. Lancet 1996; 347: 1447-49.
CHD prevention in clinical practice Kalevi
Pydr~lg
Evidence from basic, clinical, and epidemiological research continues to improve our understanding of the pathogenesis of atherosclerosis and its major clinical manifestation, coronary heart disease (CHD). In addition, we know of numerous factors that relate to the risk of a clinical C H D event: some such as lifestyles and physiological and biochemical characteristics are modifiable; others such as family history are not (panel 1). ~ Research evidence now lends strong support to the view that C H D is largely preventable by reduction of modifiable risk factors. Primary and secondary prevention are usually looked at separately. Primary prevention comprises a population strategy aiming to change, in the entire population, those lifestyles and environmental factors, and their social and economic determinants, that are the underlying causes of the mass occurrence of CHD; and a high-risk strategy, identifying symptom-free high-risk individuals and acting to reduce their risk factor levels.~ Secondary prevention is the reduction of risk factors, and other preventive measures, in patients with clinically established CHD. The individual high-risk approach and secondary prevention belong to the realm of clinical practice. International and national bodies have since the 1970s been formulating guidelines and updating them to help medical practitioners and others apply measures to prevent CHD. Three "major" risk factors--smoking, raised blood pressure, and hypercholesterolaemia--have received particular attention. Recent guidelines, however, have emphasised the total burden of risk to which an individual is exposed, rather than single risk factors. This approach acknowledges that the aetiology of CHD is multifactorial, that risk factors have a multiplicative effect, and that physicians deal with the whole person, not with isolated risk factors. The integration of C H D prevention into the practice of physicians, whether in hospitals or in primary care, has been slow; therefore, the three major European scientific societies working in cardiovascular medicine, the European Society of Cardiology (ESC), the European
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Artherosclerosis Society (EAS), and the European Society of Hypertension (ESH), appointed a joint task force to prepare recommendations that would summarise the aspects of clinical C H D prevention on which there was good agreement. The Task Force published in 1994. 2 In the United States recommendations on CHD prevention have been summarised in the report of the 27th Bethesda Conferences and are closely similar.
Priorities for CHD prevention in clinical practice The European and the US recommendations agree on priorities for CHD prevention in clinical practice: • Highest priority goes to patients with established disease because clinical trials have shown great potential for preventive action in this group. These patients are identified in ordinary clinical work and the only additional action is to persuade them to reduce their modifiable risk factors and take prophylactic drugs. • The next place goes to symptom-free individuals at high risk--for example, because of severe hypercholesterolaemia or other dyslipidaemia; diabetes or hypertension; or a cluster of risk factors. Many of these will already have been identified in the context of ordinary clinical practice. • With the progress of preventive activities, action may be extended to the closest relatives of patients with earlyonset C H D or other atherosclerotic vascular disease and, similarly, to the closest relatives of symptom-free high-risk individuals. • With further progress preventive action may finally be extended to the offer of risk-status assessment and advice to individuals not in these priority groups. This definition of priorities in clinical practice is not meant to detract from the primary approach, whereby risk factor levels are addressed in the whole population. Indeed, most cases of C H D and other atherosclerotic vascular disease arise in people with only mildly or moderately raised risk factors. The clinical approach is complementary to the population approach.
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INTERVENTIONAL CARDIOLOGY
The future of interventional cardiology Laura A Corr In less than 20 years the face of cardiology has changed. A new subspecialty of "interventional cardiology" has developed which is part medical and part surgical, and covers all the technical procedures used to treat cardiac diseases without conventional surgery. These include mitral and pulmonary valvotomies and several paediatric procedures such as closure of a patent ductus arteriosus or atrial septal defect, but by far the most common procedure is percutaneous transluminal coronary angioplasty (PTCA). The subspecialty can be traced to the day in 1929 when Forssmann showed he could place a catheter in his own heart and survive. M a n y years later, Sones, a paediatrician, accidentally injected contrast medium into the coronary tree and obtained the first coronary arteriogram. The fact that the large volume of contrast medium caused an episode of ventricular fibrillation did not discourage him from pursuing the observation and paving the way for the era of diagnostic angiography. But interventional cardiology began with Andreas Gruentzig, a young Swiss physician, who was impressed by Dotter's technique of peripheral artery dilation with rigid dilators. Working initially on his kitchen table, he developed the first balloon catheters small enough to reach into the coronary arteries. In 1977 he performed the first successful coronary artery dilation; by the millenium the rate of angioplasty worldwide will easily exceed one million per year.
associated with P T C A approach those of coronary artery bypass grafting (CABG) over a period of three years, 3 and to date the benefits accruing from coronary interventions in this group appear modest, so the cost-benefit analysis of this larger trial is likely to be unfavourable. Whether the economic drawback would slow the exponential rise in the use of angioplasty remains to be seen.
Immediate angioplasty for acute coronary syndromes Angioplasty is invaluable in patients with unstable angina who do not settle on medical therapy, often allowing rapid and complete resolution of the symptoms and early discharge from hospital. 4 In the setting of acute myocardial infarction, several small studies suggested that immediate angioplasty established reperfusion more quickly and more effectively than thrombolysis and was associated with a lower mortality2 The financial implications of this strategy are prohibitive--fully staffed interventional catheter laboratories available 24 hours a day in every district general hospital--and those responsible for the provision of health care are probably relieved to note the preliminary results of the large G U S T O II trial, which just failed to show a significant benefit for angioplasty over thrombolysis when the practice was extended outside the high-volume established interventional centres. Nonetheless, there is still a strong drive amongst trained cardiologists to introduce the policy of immediate angioplasty, particularly for young patients with large anterior infarcts.
A triumph of practice over theory Angioplasty should not work. The pathology of the atherosclerotic plaque is complex with its macrophageladen, lipid-rich core and fibrous cap that is frequently calcified. Gruentzig believed that angioplasty compressed the plaque "like footprints in the snow", but we now know that plaque compression is a minor feature and the principal mechanism of action of angioplasty is to create dissection. Pressures of 6-16 atmospheres are routinely used with the newer balloons to crack the stenoses. The endothelium is disrupted. There is substantial recoil of the dilated vessel and a vigorous migration of smooth muscle cells in response to the injury causes more than 50% restenosis in a quarter to half the vessels dilated. It is astonishing that such a crude technique actually produces clinical benefit, but P T C A is widely use d in patients with chronic stable angina and unstable angina and increasingly in acute myocardial infarction.
The role of PTCA Angioplasty versus medical therapy Many interventions are conducted in patients who would formerly have been managed on medical therapy. Two small trials have examined the benefit of P T C A in patients with chronic stable angina. In one there was a modest but significant reduction in ischaemia and improvement in wellbeing, but neither trial was of a size to detect any difference in the rate of acute myocardial infarction or death? '2 Belatedly, a larger randomised controlled trial (RITA II) to examine this question with modern angioplasty techniques is now underway. The costs
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Will angioplasty replace coronary artery bypass grafting? Much work has been done to compare the benefits of P T C A and CABG. The results of several major trials with follow-up over 1-5 years show remarkably consistent results6'7: there was no difference in the rate of death or myocardial infarction but patients were much more likely to need a subsequent procedure in the first year after P T C A and were less likely to be free of angina. Recovery was quicker after P T C A but long-term return to work was no different. The differences between the two techniques tended to diminish over time. Similarly, the benefit of lower costs associated with the initial P T C A procedure compared with CABG fell over time because of the costs of the further revascularisation procedures required. A meta-analysis of 3371 patients followed up over 2'7 years showed that 4-6% of patients undergoing P T C A and 4"4% of patients undergoing CABG died during follow-up. The combined rate of cardiac death or non-fatal myocardial infarction was 9'9% and 9"3%, respectively. 34% of P T C A patients needed a further revascularisation procedure, including 18% who subsequently undel~vent CABG. 6 The implications of these trial results for the future of interventional cardiology versus bypass surgery have been fiercely debated. Those who favour CABG point out that the trial patients were highly selected: patients with left main stem disease and many with three-vessel disease and impaired left ventricular function, for whom surgery would be expected to improve prognosis, were not
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randomised. The role of angioplasty in such patients is unknown. Even in the low-risk group who were randomised, P T C A was no safer than surgery--largely on account of uncontrolled vessel dissection. For relief of symptoms, surgery undoubtedly provided a more reliable short-term result because of the problem of restenosis after angioplasty. Conversely, those who favour P T C A point out that the short-term follow-up emphasises the problem of restenosis, which occurs within the first six months, whereas the failure rate of saphenous vein bypass grafts rises sharply only after 5-8 years. Re-do surgery carries higher risks than the first operation while re-do P T C A is no more hazardous than the primary procedure and 80% of patients in the trials were successfully managed by angioplasty alone2 These arguments largely miss the point. In clinical practice, both techniques have advantages and disadvantages and direct comparison of the two is probably inappropriate. Technical considerations based on the patter~a of disease (eg, discrete lesions versus diffuse disease, vessel tortuosity, and calcification) or the circumstances of a particular patient (age, concomitant disease) will determine the likelihood of one technique being favoured over the other in the short term. Neither mode of treatment cures the underlying disease and longterm treatment strategies will use both interventions in a complementary fashion. Furthermore, both angioplasty and surgical techniques are changing. The introduction of stenting (see below) has altered the safety and long-term efficacy of P T C A to such an extent that many of the current data on angioplasty are obsolete. Similarly, the use of limited thoracotomies for internal mammary artery grafting to the left anterior descending artery, while regarded by some as a gimmick, may yet allow the prognostic benefits of surgery to be gained without the drawbacks of sternotomies, leg wounds, and cardiopulmonary bypass. 8 The complementary role of this minimally invasive surgery and invasive cardiology is evident.
Overcoming the limitations of angioplasty Drugs and devices The angioplasty trials emphasised the limitations of the technique of simple balloon dilation--the appreciable acute complication rate due to uncontrolled vessel dissection and, more importantly, the huge clinical and economic costs of restenosis. Many years and many millions of dollars were spent searching for the solution. Basic science laboratories throughout the world developed animal models of restenosis and thousands of compounds were tested in vitro and in vivo. But despite the enthusiasm and dedication of the scientists, not one of the compounds shown to be effective in animals was effective in clinical practice. Hypotheses about the reasons for this include the differences between human atherosclerosis and the animal models, the method of delivery, and simply the concentrations of the compounds required. Meanwhile interventionists were trying new techniques aimed at debulking the plaque burden in the hope of reducing acute complications and the stimulus to restenosis. Devices such as directional coronary atherectomy became quite widely used before the large randomised CAVEAT and C C A T trials demonstrated no clinical benefit. 9'~°The use of laser energy in various forms to ablate atheromatous plaque initially attracted much excitement bu~ registry data suggested an unacceptably s24
THE LANCET
increased rate of restenosis and a recent randomised trial has also shown no benefit over plain balloon angioplasty. H Many bulky and expensive machines are now sitting forlorn and unused in the corner of catheter laboratories around the world. High-speed rotational ablation with a diamond-studded burr is said to have a niche in thin calcified vessels (which are notoriously difficult to treat by angioplasty), but again randomised trial data are lacking. Enthusiasm for such devices is waning.
The era of stenting Stents deserve to be awarded a category of their own. These small metallic mesh tubes can be crimped onto angioplasty balloons and inflated across a stenosis, embedding themselves permanently into the vessel wall and holding the artery widely open. They are easy to use and were first approved by the US Food and Drug Administration in 1992 for the management of abrupt vessel closure after PTCA. Stents are the ideal adjunct to balloon angioplasty since they seal the dissection and prevent vessel recoil. The result both angiographically and haemodyamically is very attractive. Furthermore, the large randomised B E N E S T E N T (Belgium-Netherlands Stent Study) and STRESS (Stent Restenosis Study) trials with the Palmaz-Schatz stent both showed a reduction in the need for repeated revascularisaton at six months compared with balloon angioplasty (17% vs 25%, p=0.005 in B E N E S T E N T , 10% vs 15%, p=0.06 in STRESS)32'13 This benefit is almost certainly not due to inhibition of smooth muscle proliferation, which may even be aggravated; more likely, the increased vessel lumen allows greater hypertrophy without clinical restenosis. In 1994, the FDA approved the use of the Palmaz-Schatz stent in selected patients to prevent coronary restenosis after angioplasty. The pace of change in interventional cardiology is such that even these trials are now out of date. Initial experience with stents in the late 1980s was complicated by an unacceptably high rate of stent thrombosis, so patients in the trials were treated with aspirin, dipyridamole, dextran, heparin, and warfarin in the days after stenting. Unsurprisingly, these gave rise to high rates of vascular complications at the site of the groin puncture, yet the rate of stent thrombosis remained stubbornly around 5-9%. Since then it has become apparent that stenting can be safely achieved with antiplatelet agents such as aspirin and ticlopidine alone, provided that the stents are adequately deployed24 Intravascular ultrasound has been helpful in identifying optimal expansion although it remains predominantly a research tool. The effect of this simplified regimen has been to produce an explosion in the use of stenting. Thrombosis rates now seem to be less than 1% and patients are increasingly discharged from hospital after one night, with a consequent reduction in hospital costs. '~ Stents have reduced the need for bail-out CABG to such an extent that arguments are being made for angioplasty to be performed in centres without surgical backup. Stenting is now routinely conducted in 25% of angioplasties in Europe with rates as high as 70% in some institutions, and there is no sign of any decline. Unanswered questions
Developments in technology have outpaced scientific study and the dizzying pace of change in interventional cardiology leaves many questions unanswered. Stents were
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INTERVENTIONAL CARDIOLOGY
first p u t into coronary arteries t e n years ago b u t have b e e n u s e d in massive n u m b e r s only in the past two to t h r e e years. T h e i r l o n g - t e r m efficacy and, m o r e i m p o r t a n t l y , safety r e m a i n s to b e seen. S o m e early reports suggest good o u t c o m e s at three years '~ b u t if t h e r e are adverse effects, for example due to the rigidity of the m e t a l t u b e s in the c o n s t a n t l y flexing c o r o n a r y arteries after t e n or t w e n t y years, the c o n s e q u e n c e s c o u l d b e catastrophic. In the more immediate future, the cost-benefit i m p l i c a t i o n s n e e d to b e addressed. A n g i o p l a s t y a n d s t e n t i n g are satisfying to do a n d are p o p u l a r w i t h patients a n d their general physicians alike, b e i n g relatively n o n invasive a n d often p r o d u c i n g a d r a m a t i c if s o m e t i m e s s h o r t - t e r m benefit. T h u s n o - o n e is inclined to resist t h e tide, with t h e exception o f those w h o pay for h e a l t h care w h o m a y b e f o r c e d to d o so b y s i m p l e e c o n o m i c constraints. T h e t e c h n i q u e requires expensive e q u i p m e n t a n d staff a n d hospital admission. T h e only h o p e f u l factor, albeit s o m e w h a t marginal, is t h a t c o m p e t i t i o n in the m a r k e t is intense; balloons already sell at a fraction of t h e i r original price, a n d stents, too, are likely to fall in price.
W h a t does t h e f u t u r e hold? Advances in stenting I n the developed world the incidence of ischaemic h e a r t disease is declining a n d advances in d r u g therapy, s u c h as the use of the statins to lower cholesterol, m a y have f u r t h e r impact; b u t the ageing o f the p o p u l a t i o n m e a n s t h a t i n t e r v e n t i o n a l cardiology is here to stay. T h e r e will u n d o u b t e d l y be d e v e l o p m e n t s in s t e n t design over the next few years: already the original P a l m a z - S c h a t z s t e n t has b e e n challenged by stents t h a t are m o r e flexible w h e n collapsed, provide equally strong support, a n d are m a d e in various lengths. H e p a r i n - c o a t e d stents, d e v e l o p e d d u r i n g t h e era o f aggressive a n t i c o a g u l a t i o n , s e e m to give excellent results, a l t h o u g h it is n o t clear w h e t h e r they are any better than non-coated stents when properly deployed. '~ P o l y m e r stents w h i c h w o u l d b e a b s o r b e d slowly a n d h e n c e obviate any l o n g - t e r m h a z a r d s are a n attractive c o n c e p t b u t do n o t look p r o m i s i n g w i t h c u r r e n t materials. T h e q u e s t i o n of restenosis w i t h i n stents is currently the subject of study. Several o f the devices t h a t f o u n d e r e d in c o m p a r i s o n with balloon angioplasty are b e i n g tried here b u t I suspect this is m o r e in h o p e t h a n in expectation. S o m e p r e l i m i n a r y work w i t h local intravascular irradiation to r e d u c e intimal hyperplasia looks p r o m i s i n g in animals a n d early work is u n d e r w a y in m a n . 17
The contribution of molecular cardiology P r o b a b l y the m o s t exciting d e v e l o p m e n t s will c o m e f r o m m o l e c u l a r cardiology, w h e r e advances have b e e n m a d e in the d e v e l o p m e n t of agents as adjuncts to angioplasty a n d as therapies w h e r e n e i t h e r surgery n o r angioplasty is suitable. I n 1996, two large studies of the glycoprotein IIb/IIIa a n t i b o d y c7E3 F a b (abciximab; R e o P r o ) , w h i c h is a p o w e r f u l a n t i p l a t e l e t a g e n t , were p r e s e n t e d . T h e E P I L O G a n d C A P T U R E trials h a d b e e n p r e m a t u r e l y s t o p p e d in D e c e m b e r , 1995, b y the safety a n d efficacy m o n i t o r i n g c o m m i t t e e after t h e r e c r u i t m e n t o f only 1 0 0 0 - 1 5 0 0 p a t i e n t s b e c a u s e of a h i g h l y s i g n i f i c a n t r e d u c t i o n in d e a t h a n d myocardial infarction in p a t i e n t s u n d e r g o i n g angioplasty b o t h electively a n d for u n s t a b l e a n g i n a . '~ T h i s a n t i b o d y p r e v e n t s t h r o m b o t i c vessel reocclusion a n d m a y prove useful in u n s t a b l e angina,
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t r a n s i e n t c e r e b r a l i s c h a e m i c attacks, a n d m y o c a r d i a l infarction as well as in the p r e v e n t i o n of complications of angioplasty. T h e i m p a c t o n restenosis is n o t yet known. T h e s m o o t h m u s c l e cell p r o l i f e r a t i o n u n d e r l y i n g restenosis is a n attractive target for m o l e c u l a r strategies in view o f our existing k n o w l e d g e of gene-related cellular proliferation. N a b e l a n d h e r co-workers '9 successfully established transfer o f foreign D N A to arterial walls using catheter techniques, and others have demonstrated t h e r a p e u t i c effects in a n i m a l s . T r a n s g e n e e x p r e s s i o n seems to b e transient, lasting only t h r e e weeks or so, b u t this m a y be sufficient for applications such as p r e v e n t i o n of restenosis. I s n e r a n d co-workers 2° lately r e p o r t e d clinical e v i d e n c e of a n g i o g e n e s i s i n a p a t i e n t w i t h severe peripheral ischaemia after arterial angioplasty gene t r a n s f e r of a p l a s m i d t h a t e n c o d e s for vascular endothelial g r o w t h factor. T h e d e v e l o p m e n t of t h r e e spider a n g i o m a s distal to the site of gene transfer is strong, if indirect, evidence of gene expression. T h i s t e c h n i q u e could have exciting implications for m a n y p a t i e n t s with extensive a n d distal disease for w h o m n e i t h e r C A B G n o r angioplasty has m u c h to offer at present.
And n e x t . . . ? F u r t h e r d e v e l o p m e n t of existing t e c h n i q u e s will have only m a r g i n a l impact. T h e large group of patients w h o die s u d d e n l y of a n a c u t e m y o c a r d i a l i n f a r c t i o n w i t h o u t r e a c h i n g hospital m u s t b e t h e next target for cardiologists, if we look for a substantial r e d u c t i o n of mortality from i s c h a e m i c h e a r t disease. M y o c a r d i a l i n f a r c t i o n is frequently related to a vessel s e g m e n t t h a t was n o t severely s t e n o s e d b e f o r e t h e p l a q u e r u p t u r e o c c u r r e d ; lipid l o w e r i n g s e e m s to r e d u c e p l a q u e v u l n e r a b i l i t y to d i s r u p t i o n r a t h e r t h a n p l a q u e size a n d m a y have a n i m p o r t a n t role to play h e r e . F o r the i n t e r v e n t i o n a l cardiologist, t h e task is to l e a r n to identify at-risk plaques, perhaps using intravascular ultrasound or m i c r o t h e r m i s t o r s , z' a n d t h e n to t e s t w h e t h e r early i n t e r v e n t i o n c a n alter the n a t u r a l history of the disease. T h e challenge is formidable.
References 1 Parisi AF, Folland ED, Hartigan P, oll behalf of the Veterans Affairs ACME investigators. A cmnparison of angioplasty with medical therapy in the treatment of single vessel coronary artery disease. N Engl timed 1992; 326: 10-16. 2 SieversB, Hamm C, Herzner AE. Medical therapy versus PTCA: a prospective, randomised trial in patients with asymptomatic coronary single vessel disease. Circulation 1993; 88 (part II): 1-297. 3 Wientraub WS, Maudlin PD, Becket E, Kosinski AS, King SB III. A comparison of the costs of and quality of life after coronary angioplasty or coronary surgery for multivessel coronary arter disease. Results from the Emory Angioplasty versus Sm'gery Trial (EAST). Circulation 1995; 92: 2831-40. BentivoglioLG, Detre K, Yeh W, Williams DO, Kelsey SF, Faxon DP. Outcome of percutaneous transluminat coronary angioplasty in subsets of unstable angina pectoris. A report of the 1985-1986 National Heart, Lung, and Blood Institute Percutaneous Transluminal Coronary Angioplasty Registry. ,yAm Coll Cardio11994; 24:1195-206. O'Neill WW, Zijlstra F, Suryapranata H, Timmis GC, Grines CL. Meta-analysis of the PAMI and Netherlands randomised trials of primary angioplasty versus thrombolytic therapy for acute myocardial infarction. Circulation 1993; 88: 1-106. Pocock St, Henderson RA, Rickards AF, et al. Meta-analysis of randomised trials comparing coronary angioplasty with bypass surgery. Lancet 1995; 346: 1184-89. The Bypass Angioplasty Revascularisation Iaavestigation(BARI) Investigators. Comparison of coronary bypass surgery with angioplasty in patients with multivessel disease. N EngltiMed 1996; 335: 217-25. Calafiore AM, Angelini GD. Left anterior small thoracotomy (LAST) for coronary artery revascularisation. Lancet 1996; 347: 263-6,t.
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Topol EJ, Leya F, Pinkerton CA, et al. A comparison of directional atherectomy with coronary angioplasty in patients with coronary artery disease. N EngIJ Med 1993; 329: 221-27. Adelman AG, Cohen EC, Kimball BP, et ak A comparison of directional atherectomy with balloon angioplasty for lesions of the left anterior descending coronary artery. N EnglJMed 1993; 329: 228-33. Appelman YEA, Pick JJ, Stril~verda S, et al. Randomised trial of excimer laser angioplasty versus balloon angioplasty for treatment of obstructive coronary artery disease. Lancet 1996; 347: 79-84. Serruys PW, de Iaegere P, Kiemeneij F, et al. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. N E n g l J M e d 1994; 331: 489-95. Fischman D, Leon MB, Balm DS, et al. A randomised comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. N EnglJ ivied t994; 331: 496-501. Corr LA. Is anticoagulation for intracoronary stenting justified? Eur HeartJ 1996; 17: 1296. Kimura T, Yokoi H, Nakagawa Y, et al. Three-year follow-up after implantation of metallic coronary-artery stents. N Engl J Med 1996; 334: 561-66.
THE LANCET 16 Serruys PW, Emanuelsson H, van der Giessen W, et al. Heparincoated Pahnaz-Schatz stents in h u m a n coronary arteries. Early outcome of the B E N E S T E N T - I I pilot study. Circulation 1996; 93: 412-22. 17 Tierstein PS, Massullo V, Jani S, et al. A randomised, clinical trial of radiation therapy to reduce restenosis following coronary stenting-early results. J A m Coll Cardiol t996; 27:15A. 18 Van der Werf F. More evidence for a beneficial effect of platelet glycoprotein IIb/IIIa-blockade during coronary interventions. Latest results from the E P I L O G and C A P T U R E trials. EurHeartJ 1996; 17: 325-26. 19 Nabel EJ, Plautz G, Nabel GJ. Site-specific gene expression in vivo by direct gene transfer into the arterial wail. Science 1990; 249: 1285-88. 20 Isner JM, Pieczek A, Schainfeld R~ et al. Clinical evidence of angiogenesis after arterial gene transfer o f p h V E G F 1 6 5 in patient with ischaemic limb. Lancet 1996; 348: 370-74. 21 Casscells W, Hathorn B, David M, et al. Thermal detection of ceUular infiltrates in living atherosclerotic plaques: possible implications for plaque rupture and thrombosis. Lancet 1996; 347: 1447-49.
CHD prevention in clinical practice Kalevi
Pydr~lg
Evidence from basic, clinical, and epidemiological research continues to improve our understanding of the pathogenesis of atherosclerosis and its major clinical manifestation, coronary heart disease (CHD). In addition, we know of numerous factors that relate to the risk of a clinical C H D event: some such as lifestyles and physiological and biochemical characteristics are modifiable; others such as family history are not (panel 1). ~ Research evidence now lends strong support to the view that C H D is largely preventable by reduction of modifiable risk factors. Primary and secondary prevention are usually looked at separately. Primary prevention comprises a population strategy aiming to change, in the entire population, those lifestyles and environmental factors, and their social and economic determinants, that are the underlying causes of the mass occurrence of CHD; and a high-risk strategy, identifying symptom-free high-risk individuals and acting to reduce their risk factor levels.~ Secondary prevention is the reduction of risk factors, and other preventive measures, in patients with clinically established CHD. The individual high-risk approach and secondary prevention belong to the realm of clinical practice. International and national bodies have since the 1970s been formulating guidelines and updating them to help medical practitioners and others apply measures to prevent CHD. Three "major" risk factors--smoking, raised blood pressure, and hypercholesterolaemia--have received particular attention. Recent guidelines, however, have emphasised the total burden of risk to which an individual is exposed, rather than single risk factors. This approach acknowledges that the aetiology of CHD is multifactorial, that risk factors have a multiplicative effect, and that physicians deal with the whole person, not with isolated risk factors. The integration of C H D prevention into the practice of physicians, whether in hospitals or in primary care, has been slow; therefore, the three major European scientific societies working in cardiovascular medicine, the European Society of Cardiology (ESC), the European
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Artherosclerosis Society (EAS), and the European Society of Hypertension (ESH), appointed a joint task force to prepare recommendations that would summarise the aspects of clinical C H D prevention on which there was good agreement. The Task Force published in 1994. 2 In the United States recommendations on CHD prevention have been summarised in the report of the 27th Bethesda Conferences and are closely similar.
Priorities for CHD prevention in clinical practice The European and the US recommendations agree on priorities for CHD prevention in clinical practice: • Highest priority goes to patients with established disease because clinical trials have shown great potential for preventive action in this group. These patients are identified in ordinary clinical work and the only additional action is to persuade them to reduce their modifiable risk factors and take prophylactic drugs. • The next place goes to symptom-free individuals at high risk--for example, because of severe hypercholesterolaemia or other dyslipidaemia; diabetes or hypertension; or a cluster of risk factors. Many of these will already have been identified in the context of ordinary clinical practice. • With the progress of preventive activities, action may be extended to the closest relatives of patients with earlyonset C H D or other atherosclerotic vascular disease and, similarly, to the closest relatives of symptom-free high-risk individuals. • With further progress preventive action may finally be extended to the offer of risk-status assessment and advice to individuals not in these priority groups. This definition of priorities in clinical practice is not meant to detract from the primary approach, whereby risk factor levels are addressed in the whole population. Indeed, most cases of C H D and other atherosclerotic vascular disease arise in people with only mildly or moderately raised risk factors. The clinical approach is complementary to the population approach.
Vol 348 • November
1996