Shahed Islam1, Adam Timmis1
1 NIHR Biomedical Research Unit, Barts and the London School of Medicine and Dentistry, London Chest Hospital, London, UK
* Islam S, Timmis A. Heart Published Online First: Heart 2013;0:1–6. doi:10.1136/heartjnl-2013-304593
Professor Adam Timmis, NIHR Biomedical Research Unit, Barts and the London School of Medicine and Dentistry, London Chest Hospital, London E2 9JX, UK; email@example.com
Received 4 July 2013. Accepted 13 August 2013.
CORONARY HEART DISEASE IN DECLINE
Epidemiological data from Europe, the USA and elsewhere in the developed world show a steep decline in coronary heart disease (CHD) mortality during the last 40 years1. Concern about levelling of mortality rates in younger adults2 has been somewhat alleviated by data from The Netherlands showing that in men aged <55 years, rates of decline have again accelerated, increasing from only 16% in 1993-1999 to 46% in 1999-20073.
A similar pattern was observed in young women with rates of decline of 5% and 38% during the same time periods. This is encouraging, particularly in the context of data from Denmark and the UK showing declining mortality and also a sharp fall in standardized incidence rates for acute myocardial infarction indicating that coronary prevention, as well as acute treatments, has contributed to recent mortality trends4,5. Meanwhile an Australian study reminds us that myocardial infarction is but one of several manifestations of cardiovascular disease by reporting that decreasing incidence and recurrence rates for hospitalized CHD from 2000 to 2007 have also been seen for cerebrovascular and peripheral arterial disease6.
However, the epidemiological news is not all good, and data from the UK show that the pernicious relationship between socioeconomic status (SES) and CHD has shown no tendency to go away in recent years, the gradients between top and bottom SES quintile groups for hospital admissions remaining essentially unchanged across the age range7. Whether this has contributed to the almost 3-fold risk of myocardial infarction associated with stillbirth and 9-fold risk associated with recurrent miscarriage in a recent German study is unclear because the investigators made no adjustment for SES8. Nor is it clear if SES has contributed to the persistent ethnic differences in both US and UK studies of CHD mortality although other factors appear also to be important. Thus, African–American men have greater exposure to CHD risk factors than Caucasians and, when adjustment is made for this, their susceptibility to CHD is no greater, although mortality rates are twice as high9. For African-American women, incidence and mortality rates are higher than their Caucasian counterparts. These ﬁndings suggesting that exposure to risk factors contributes to ethnic differences in the incidence of CHD are to some extent reﬂected in a recent report from the Health Survey for England in which 13 293 Caucasian and 2120 S Asians consented to mortality follow-up10. Physical inactivity was more frequent in S Asians compared with Caucasians (47% vs 28%) and explained >20% of their excess CHD mortality. Certainly, the emerging consensus is that the excess CHD mortality among UK S Asians is driven almost entirely by their increased susceptibility to disease and not by increased case-fatality rates11.
DIAGNOSIS OF STABLE CORONARY ARTERY DISEASE
The recent AHA/ACC guideline update12 emphasized the importance of individualizing the diagnostic workup based on the estimated probability of coronary artery disease. In this respect, it mirrored an earlier National Institute of Clinical Excellence (NICE) guideline on chest pain diagnosis13, but there were important differences in the recommendations for non-invasive testing, the new AHA/ ACC guideline preferring the exercise ECG as the initial diagnostic approach for most patients, (NICE had previously counselled against use of the exercise ECG based on its relatively poor diag- nostic performance) with pharmacologic radionuclide, cardiac MRI or stress echocardiography testing in reserve for patients unable to exercise. Recommendations for cardiac CT coronary angiography (CTCA) were cautious, and invasive angiography was recommended for diagnostic purposes only if the results of non-invasive testing suggested a high likelihood of severe 3-vessel or left main coronary artery disease, and the patient was willing to undergo revascularizations. In general, therefore, the AHA/ACC guideline update was less prescriptive than the earlier NICE guideline, perhaps partly because it put less emphasis on the cost effectiveness of its recommendations.
MANAGEMENT OF STABLE CORONARY ARTERY DISEASE
The recent NICE guideline14 recommended initial treatment with a short-acting nitrate and a β-blocker and/or a calcium channel blocker for control of angina plus aspirin and a statin for secondary prevention. Lifestyle measures were also emphasized. For patients with continuing symptoms cardiac catheterization with a view to revascularization was recommended, additional antianginal treatment (long-acting nitrates or one of the newer agents) only being indicated for patients unsuitable for revascularization. It was further recommended that the mode of revascularization (percutaneous coronary intervention (PCI) versus coronary artery bypass grafting (CABG)) should best be determined by a multidisciplinary group, a recommendation that has also been emphasized by European guideline groups15, bearing in mind the potential for prognostic beneﬁt from CABG in patients with complex multivessel and left main stem disease16, particularly those with diabetes. For patients with symptoms adequately controlled with medical treatment, the guideline recommended discussion of the potential for prognostic improvement with CABG. Those patients prepared to proceed to CABG might then be offered diagnostic cardiac catheterization to rule out complex multivessel and left main stem disease, which a recent meta-analysis reported in as many as 36% (18.5-48.8%) of cases of stable coronary disease selected for cardiac catheterization17.
SECONDARY PREVENTION OF STABLE CORONARY DISEASE
The scope for improving secondary prevention in patients with stable coronary artery disease has been emphasized in two recent reports. In The multinational REduction of Atherothrombosis for Continued Health (REACH) Registry, 20 588 symptomatic patients were analyzed for ‘good control’ of cardiovascular risk factors, deﬁned as three to ﬁve of systolic blood pressure <140 mm Hg, diastolic blood pressure <90 mm Hg, fasting glycaemia <110 mg/dL, total cholesterol <200 mg/dL, non-smoking18. Only 59.4% had good control of risk factors at baseline, but this was associated with lower mortality (OR 0.89; 95% CI 0.79 to 0.99) at 36 months, compared with poor control. In the UK ASPIRE-2-PREVENT survey, 676 patients with CHD (25.6% women) had the following rates of major risk factors: smoking 14.1%, obesity 38%, physical inactivity 83.3%, blood pressure ≥130/80 mmHg, total cholesterol ≥4 mmol/L and diabetes 17.8%, leading the authors to conclude that there is considerable potential for reducing cardiovascular risk in these patients and thereby improve prognosis19.
Clopidogrel. The availability of low-cost generic clopidogrel prompted a NICE review of its cost effectiveness which recommended it should now supersede aspirin in certain high-risk groups, namely patients with multivascular disease, peripheral vascular disease and myocardial infarction20. However, clopidogrel is metabolized by enzymes in the hepatic cytochrome P450 (CYP) system, and variability in its antiplatelet activity may occur because the activity of these enzymes is inﬂuenced by common genetic variations, and also by a number of commonly used drugs. Several studies have reported loss-of-function alleles in CYP2C19 that result in reduced activation of clopidogrel21 and a modest lowering of antiplatelet activity22 which have been associated with an increased risk of cardiovascular events in some meta-analyses23. Conversely, gain-of-function alleles have been associated with reduced cardiovascular risk among clopidogrel-treated patients24 A recent meta-analysis, however, has commented on the tendency of small studies to bias conclusions about the way genetic variants inﬂuence clinical outcomes, and in larger studies of clopidogrel therapy with ≥200 outcome events found no effect of loss-of-function alleles on cardiovascular risk25. At present, therefore, there seems to be no compelling indication for genetic testing to guide clopidogrel treatment although the topic remains a subject of ongoing debate. Also debated is the interaction of clopidogrel with some commonly used drugs, particularly proton pump inhibitors (PPI) and amlodipine. A recent meta-analysis of studies of PPIs in patients treated with clopidogrel found clear evidence of reduced platelet activity but although clinical outcomes appeared adversely affected by the interaction, the authors urged cautious interpretation, pointing out the heterogeneity caused by retrospective studies. When analysis was restricted to prospective studies of PPIs and clopidogrel, adverse clinical consequences could no longer be demonstrated (OR 1.13 (0.98 to 1.30))26. Similarly, the clinical impact of amlodipine on responsiveness to clopidogrel remains uncertain. Certainly, there is evidence of interaction, and in one study of 1258 patients receiving clopidogrel, amlodipine administration was associated with higher on treatment platelet reactivity only in those patients with a loss-of-function P450 (CYP) genotype (249±83 vs 228±84 P2Y12 reaction units), and this was associated with a higher incidence of cardiovascular events (4.6% vs 0.6%)27. However, in a more recent randomized trial, platelet function in 98 patients with stable coronary artery disease taking clopidogrel was similar regardless of amlodipine therapy28. At present, therefore, there is no guideline recommendation about concomitant prescription of these drugs in patients taking clopidogrel, statins, niacin and cholesterol ester transfer protein (CETP) inhibitors. The beneﬁts of statins for secondary prevention in patients with stable coronary artery disease are well established. Cardiovascular endpoints are reduced in proportion to the degree of LDL-cholesterol reduction, probably in response to stabilisation and regression of atheromatous plaque. The capacity for plaque regression has recently been conﬁrmed by serial IVUS examination in 1039 patients with stable coronary disease randomized to rosuvastatin 40 mg daily or atorvastatin 80 mg daily29. Atheroma volume during the 2-year monitoring period decreased by an average of about 1% in both groups, more than previously reported with less intensive statin regimens. However, additional clinical beneﬁts of niacin have now been unequivocally ruled out in the AIM-HIGH trial in which 3414 patients with stable cardiovascular disease taking statins were randomized to receive niacin (n=1718) or placebo (n=1696)30. Although niacin signiﬁcantly increased HDL cholesterol and lowered triglycerides, differences in the primary endpoints (a composite of adverse coronary events, strokes and revascularization) were negligible, occurring in 16% of patients in each group. The trial was stopped after an average follow-up of 3 years when it became clear HDL raising therapy with niacin was clinically ineffective. All hopes for HDL raising therapy are now invested in CETP inhibitors, and despite safety concerns following the ILLUMINATE trial of torcetrapib31, in which treatment was associated with increased mortality despite substantial HDL elevations, other CETP inhibitors are now entering phase III trials. A recent randomized trial of dalcetrapib in patients with acute coronary syndromes was disappointing with no reduction in the risk of recurrent coronary events despite a >30% increase in HDL levels in the treatment group32. An efﬁcacy and safety trial of anacetrapib in patients with, or at high risk of, stable coronary disease was favorable, although not powered for clinical outcomes33, and evacetrapib has now entered the arena with a recent study showing effective HDL raising without the adverse effects on blood pressure seen with torcetrapib and, to a lesser extent, dalcetrapib34. Whether any of these CETP inhibitors will improve clinical outcomes, however, remains unknown.
Novel lipid-lowering drugs in clinical translation. Conventional lipid-lowering therapies, even when combined with LDL-apherisis, are often insufﬁcient to treat to guideline targets patients with familial hypercholesterolaemia (FH), an autosomal dominant disorder of lipid metabolism associated with accelerated coronary disease35. There is, therefore, considerable interest in novel therapies currently under investigation, particularly lomitapide, an oral inhibitor of microsomal transfer protein and monoclonal antibodies against PCSK9. A phase II study of lomitapide in homozygous FH showed a 50% reduction in LDL-cholesterol and, although gastrointestinal side effects were common, a useful role for the drug seems likely in these homozygous patients36. PCSK9 inhibitors have also produced 50-60% reductions in LDL-cholesterol values in clinical studies when added to statins and ezetimibe, but unlike lomitapide, are probably mainly effective in heterozygotic FH because they act through interference with LDL receptors which are dysfunctional or completely absent in homozygotes37,38. The expectation is that application of these new drugs will allow most patients with FH to achieve target concentrations of LDL cholesterol. An important component of FH management involves identiﬁcation of other affected family members, and cascade screening using genetic testing has been reported as cost effective39. However, recent evidence suggests that polygenic disorders account for an appreciable proportion of FH cases40, and this will limit the effectiveness of cascade screening to relatives of mutation-positive (monogenic) cases. In other patients, with cholesterol levels consistent with an FH genotype, more conventional primary care strategies41 should remain the screening tool of choice, at least for the time being.
REVASCULARISATION IN STABLE CAD
Percutaneous coronary intervention. The COURAGE trial was a game-changer, showing that coronary stenting in patients with stable angina did not improve cardiovascular outcomes compared with optimal medical therapy (OMT) while quality-of-life beneﬁts were short-lived42,43. Now available is a meta-analysis comparing contemporary medical therapy and PCI in eight randomized trials involving 7229 patients with stable CAD44. Again, cardiovascular outcomes between the groups were similar during follow-up for an average 4.3 years with no signiﬁcant clinical beneﬁt for PCI, risks of death (8.9% vs 9.1%) and non-fatal MI (8.9% vs 8.1%) being nearly identical with medical therapy, while differences in unplanned revascularization (21.4% vs 30.7%) and persistent angina (29% vs 33%) were small and insigniﬁcant. The data support recent guideline recommendations for treatment of stable angina (see above), and have been used to challenge those clinicians who continue to offer PCI to patients not receiving OMT45. However, FAME-II has now provided some support for an early interventional approach in a randomized comparison of OMT and PCI using drug-eluting stents guided by fractional ﬂow reserve (FFR)46. The study was stopped 17 months earlier than planned because the composite endpoint (all-cause mortality, non-fatal MI, urgent revascularization) occurred in 4.3% of the PCI group compared with 12.7% of the non-PCI (OMT) group. Relief of angina was also more effective in the PCI group. Already, PCI guided by FFR has become a recommended strategy in stable coronary artery disease but some feel this is premature47. Thus, the treatment difference in FAME-II was driven solely by a reduction in urgent revascularization (49 in the OMT alone group; 7 in the FFR-PCI group (HR=0.13, 95% CI 0.06 to 0.30), while the 33 deaths and non-fatal MIs were distributed fairly evenly between the groups. Moreover, the majority of patients undergoing ‘urgent’ revascularization lacked objective ﬁndings of high-risk ischaemia or threshold biomarker elevations, raising concerns of biased selection of patients for invasive management during follow-up. Nevertheless, the argument in favor of interventional management as an initial strategy in stable angina has undoubtedly been strengthened by FAME-II, but ﬁnal answers to the debate may have to await the ﬁndings of the ongoing International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA Trial; ClinicalTrials.gov number, NCT 01471522), comparing effects of revascularization (PCI or CABG) combined with OMT, with OMT alone on cardiovascular death, or MI in patients with stable CAD, and objective evidence of myocardial ischaemia.
Coronary artery bypass surgery. Updated US guidelines48 have endorsed the NICE recommendation of a multidisciplinary team approach to adjudicating revascularization decisions in patients with complex coronary disease, encouraging application of SYNTAX and other scoring systems in arriving at an appropriate decision49. The potential for CABG compared with PCI to improve prognosis in patients with left main and multivessel CAD is supported by recent cohort studies50,51, and now available are the 5-year follow-up data from SYNTAX in which major adverse cardiac and cerebrovascular events (MACCE) were 26•9% in the CABG group and 37-3% in the PCI group, driven largely by lower rates of non-fatal myocardial infarction and repeat revascularization for CABG, with no signiﬁcant difference in all-cause mortality and stroke compared with PCI52. The beneﬁts of CABG were particularly evident in patients with intermediate and high SYNTAX scores, there being no signiﬁ- cant difference in outcomes between revascularization strategies for patients with low SYNTAX scores. Any question about the preferred revascularization strategy in patients with diabetes and mutlivessel coronary artery disease has now been answered by the FREEDOM TRIAL which randomized 1900 patients on OMT to either PCI with drug-eluting stents or CABG53. After a median follow-up of 3.8 years, the primary outcome, a composite of death from any cause, non-fatal myocardial infarction, or non-fatal stroke, occurred in 26.6% of the PCI group and 18.7% of the CABG group. The authors concluded that CABG is superior to PCI in patients with diabetes and multivessel disease. There is less certainty about the preferred revascularization strategy in left main coronary disease, the SYNTAX investigators reporting similar outcomes for PCI and CABG, a ﬁnding consistent with other contemporary studies that identify stenting as a reasonable strategy in appropriately selected cases, even though the need for repeat revascularization is almost invariably higher compared with CABG54,55.
Surgical technique has come under considerable scrutiny recently. Concerns about the potential adverse effects of endoscopic versus open saphenous vein harvesting have been based largely on a non-randomized cohort study of 1817 patients in whom rates of vein graft failure at 1 year were 47% vs 38%, and rates of death, myocardial infarction or revascularization at 3 years were 20.2% vs 17.4% for endoscopic versus open saphenous vein harvesting56. This led NICE to recommend caution in use of the endoscopic technique57, but such concerns have now been allayed by the results of two large cohort studies. In the US study of 235 394 Medicare CABG patients in the Society of Thoracic Surgeons (STS), national database mortality rates were similar regardless of harvesting technique, while rates of harvest site complications were lower for the endoscopic technique58. A UK study of 4702 CABG patients reported similar ﬁndings with no differences in in-hospital mortality (0.9% vs 1.1%, p=0.71) or midterm mortality (HR 1.04; 95% CI 0.65 to 1.66) for endoscopic versus open vein harvesting59.
Also under scrutiny have been the relative beneﬁts of off-pump and on-pump CABG. Each has its proponents60,61, but the results of randomized outcome trials have failed to show any clear advantage for off-pump CABG, the 3-year results of the Best Bypass Surgery Trial showing no signiﬁcant difference in the primary composite outcome of MACCE compared with on-pump CABG, but a tendency towards higher mortality62. This may reﬂect, at least in part, differences in graft patency rates favoring on-pump procedures, the ROOBY trial reporting rates of 91.4% vs 85.8% for arterial grafts and 80.4% vs 72.7% for saphenous vein grafts in on-pump compared with off-pump patients63. Particularly disappointing has been the failure of off-pump surgery to reduce cerebral injury, but a randomized comparison of minimal (MECC) versus conventional (CECC) extracorporeal circulation in 64 patients undergoing CABG has been more promising64. MECC was associated with improved cerebral oxygen delivery during surgery, and neurocognitive performance at 3 months was better when compared with CECC.
REMOTE ISCHAEMIC PRECONDITIONING FOR TREATMENT OF STABLE CORONARY DISEASE
Its proponents see remote ischaemic preconditioning (RIPC) as a useful and inexpensive means of improving outcomes across a range of cardiovascular disorders. They must be frustrated, therefore, by the technique’s failure to penetrate clinical practice, conﬂicting reports of its efﬁcacy and mechanistic uncertainty combining to undermine clinical conﬁdence in the utility of RIPC. Some recent randomised trials have been favorable, reporting protection against contrast-induced nephropathy during cardiac catheterization65 and reduction in myocardial injury during heart valve surgery66. Perhaps the most favorable has been a randomized trial of prehospital RIPC in 333 patients with STEMI who underwent primary PCI67. The group with RIPC showed a signiﬁcant improvement in myocardial salvage index compared with the group without (0.75 vs 0.55) although the trial was not powered for coronary events. Against this must be set a negative trial of RIPC in a group of patients undergoing CABG68, but this is unlikely to be the last word, and already a meta-analysis of nine studies including 704 patients has concluded that RIPC signiﬁcantly reduces troponin release during CABG69. Mechanistic studies of interest include one crossover study in patients with stable coronary artery disease in which RIPC reduced platelet activation during exercise testing without protecting against ischaemic ECG changes70. In another study of forearm blood ﬂow using venous plethysmography in healthy volunteers, RIPC protected against impaired endothelium-dependent vasomotor function induced by ischaemia71. However, this protection was unaffected by infusion of a bradykinin B2 receptor antagonist, leading the authors to conclude that bradykinin is not a mediator of RIPC.
PROGNOSTIC BIOMARKERS IN STABLE CAD
Circulating biomarkers. Interest in circulating cardiovascular biomarkers has never been higher, and methodological papers have been developed to alert researchers to the standards necessary for proper evaluation of their prognostic utility72,73. However, a systematic review of 83 CRP studies was critical of their general quality and concluded that ‘multiple types of reporting bias, and publication bias, make the magnitude of any independent association between CRP and prognosis among patients with stable coronary disease sufﬁciently uncertain that no clinical practice recommendations can be made’74. The same authors were equally critical of 19 BNP studies in patients with stable coronary disease, reporting that clinically useful measures of prediction and discrimination were generally unavailable, and concluding that the unbiased strength of association of BNP with prognosis in stable coronary disease is unclear75. The availability of high-sensitivity assays has seen renewed interest in troponins as markers of risk in stable coronary disease, a US study of 984 patients in the Heart and Soul Study reporting that each doubling in hs-cTnT level is associated with a 37% higher rate of cardiovascular events76. Meanwhile the PEACE investigators have reported that among 3623 patients with stable coronary artery disease, hs-cTNI is independently associated with cardiovascular death or heart failure (HR 1.88 (1.33 to 2.66; p<0.001)), the association with non-fatal myocardial infarction being weaker (1.03 to 2.01; p=0.031)77. Evidence from CTCA suggests that clinically silent rupture of non-calciﬁed plaque with subsequent microembolisation is a likely pathophysiological mechanism of troponin elevation78 but it is too soon to know whether it will have a clinical role in the prognostic assessment of stable coronary artery disease. The same applies to the mid-regional portion of proadrenomedullin and other biomarkers currently under investigation79.
Vascular biomarkers. Carotid intima-media thickness (cIMT) is well established as a predictor of cardiovascular events in the general population and, more weakly, in patients with stable coronary artery disease80. Its predictive value may be enhanced by additional consideration of the extent of carotid plaque allowing derivation of the ‘total burden score’ which was shown by Chinese investigators to improve the prediction of the 5-year risk of cardiovascular endpoints compared with cIMT alone81. Certainly, the value of cIMT alone for cardiovascular risk prediction in the general population is under question following a large meta-analysis of participant-level data in 45 828 individuals in which cIMT added almost nothing to the Framingham Risk Score82. Further questions have been raised by another meta-analysis of participant-level data which included 36 984 individuals followed-up for an average of 7 years83. The investigators showed no association between progression of cIMT and risk of cardiovascular events, questioning the validity of using changes in cIMT as a surrogate endpoint in trials of cardiovascular risk.
Calcium and parathyroid hormone. Studies suggesting that people who take calcium supplements may be increasing their risk of myocardial infarction84,85 have stimulated interest in serum calcium and its relation to cardiovascular events in patients with CHD. A recent study has conﬁrmed that vitamin D, parathyroid hormone and calcium show association with cardiovascular risk factors in US adolescents86, and now we have data in 1017 patients with stable coronary artery disease followed-up for a median of 8.1 years, suggesting that high calcium levels, but not high phosphate levels, might be asso- ciated with all-cause and cardiovascular mortality (HR 2.39 to 4.66))87. The mechanism of this association is unclear, but the demonstration in the same cohort of a similar association between high parathyroid hormone and cardiovascular mortality may implicate calcium mobilisation from bone on the causal pathway88.
Contributors: SI and AT contributed equally to the preparation and writing of this review article.
Competing interests: None.
Provenance and peer review: Commissioned; internally peer reviewed.
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