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Heart. 2007 September; 93(9): 1159–1160.
PMCID: PMC1955001

Cardiovascular highlights from non‐cardiology journals

Monitoring Editor: Alistair Lindsay


SWISSI II bolsters the case for an early interventional approach

Even after surviving myocardial infarction (MI), subclinical or “silent” ischaemia is common. The effect of percutaneous coronary intervention (PCI) on the long‐term prognosis of these patients is not known.

The SWISSI II (Swiss Interventional Study on Silent Ischaemia Type II) trial was an unblinded controlled trial that randomised patients with a recent MI to PCI aimed at full revascularisation (n = 96), or to intensive anti‐ischaemic drug treatment (n = 105). All patients had silent myocardial ischaemia verified by stress imaging, and one‐ or two‐vessel coronary disease. The main outcome measure was survival free of major adverse cardiac events (cardiac events, non‐fatal MI, and/or symptom‐driven revascularisation).

The mean follow‐up was 10.2 years; 27 major adverse cardiac events occurred in the PCI group and 67 in the anti‐ischaemic drug treatment group (adjusted hazard ratio = 0.33; p<0.001). Patients in the PCI group also had lower rates of ischaemia (11.6% vs 28.9%; p = 0.03) despite receiving fewer drugs overall. Left ventricular ejection fraction was preserved in PCI patients (mean of 53.9% at baseline to 55.6%), but decreased significantly in patients receiving drug treatment (mean 59.7% at baseline to 48.8%).

Therefore in this trial, PCI compared with anti‐ischaemic drug treatment reduced the long‐term risk of major cardiac events. These findings do not necessarily contradict those of the recent COURAGE study, which, in contrast, recruited patients with stable angina. It should be noted that recruitment to the trial began over 16 years ago, and that many patients were treated by balloon angioplasty only. Furthermore statin and ACE inhibitor treatments were used far less frequently than they are today.

[filled triangle] Erne P, Schoenenberger AW, Burckhardt D, et al. Effects of percutaneous coronary interventions in silent ischaemia after myocardial infarction. The SWISSI II Randomized Controlled Trial. JAMA 2007;297:1985–991.

Off‐label use of DES

How effective and safe are drug‐eluting stents (DES) when used “off‐label”? Two papers from the Journal of the American Medical Association aimed at answering this question. Beohar and colleagues looked at 1‐year results of the DES‐COVER registry, involving 7752 patients treated with percutaneous coronary intervention (PCI) from 140 American academic and community hospitals. This study aimed at determining the frequency, safety and effectiveness of DES when used for off‐label (restenosis, bypass graft lesion, long lesions, vessel size apart from information for use recommendation) and untested (left main, ostial, bifurcation or total occlusion lesions) indications. The main outcome measures were the frequency of off‐label and untested use, 1‐year repeat target vessel revascularisation, and a composite of death, myocardial infarction (MI), or stent thrombosis at in‐hospital follow‐up and during 1 year of follow‐up.

Overall, 5541 patients received DES, of whom 2588 (47%) received stents for off‐label or untested indications. No difference was observed in the risk of death, MI, or stent thrombosis while in hospital. However, at 30 days the risk of the composite end point was significantly higher with off‐label use (adjusted hazard ratio (HR) = 2.08; p = 0.005) but not untested use (adjusted HR = 1.45; p = 0.23). When these early events were excluded, the composite end point was not different at 1 year with either off‐label or untested use. But at 1 year significantly higher rates of target vessel revascularisation were associated with off‐label use (adjusted HR = 1.49; p = 0.005) and untested use (adjusted HR = 1.49; p = 0.01).

These results suggest that in contemporary practice in the United States, off‐label and untested use of DES is common, and that their short‐ and long‐term effectiveness is lower than with on‐label use. It should be noted that absolute event rates remained low, both in hospital and at 12 months after PCI.

In a separate study, Win et al reported 1 year results from the Evaluation of Drug Eluting Stents and Ischaemic Events (EVENT) registry. A total of 3323 patients were recruited from 42 American hospitals, all of whom had received at least one DES for a reason other than acute ST‐segment elevation myocardial infarction. The composite outcomes included death, MI or target vessel revascularisation during the index admission and death, MI, or target lesion revascularisation at 1 year.

A total of 1817 (54.7%) were found to have at least one off‐label characteristic. During the index hospitalisation, the composite clinical outcome occurred in 198 (10.9%) patients in the off‐label group and 76 (5.0%) patients in the on‐label group (p<0.001); this was also true at 1 year (17.5% vs 8.9%; p<0.001). Stent thrombosis was also noted to occur more frequently among patients in the off‐label group both during the initial hospitalisation (8 patients vs 0) and at 1 year (20 patients vs 13).

Both these studies report a very high off‐label use of DES, and higher acute and late ischaemic complication risk for off‐label use when compared with on‐label. Stent thrombosis occurred more commonly among patients receiving DES for off‐label indications, even after adjustment for dual antiplatelet therapy. Although based on registry data, rather than randomised controlled trials, the data from these papers suggest caution in off‐label use of DES. However, this “off‐label” use has not been compared with the result when bare‐metal stents are used for such indications—all of which are known to be associated with worse outcomes after PCI. Off‐label use of DES mirrors the fact that few “real‐life” patients are like those in randomised trials.

[filled triangle] Beohar N, Davidson CJ, Kip KE, et al. Outcomes and complications associated with off‐label and untested use of drug‐eluting stents. JAMA 2007;297:1992–2000.

[filled triangle] Win HK, Caldera AE, Maresh K, et al. EVENT registry investigators. Clinical outcomes and stent thrombosis following off‐label use of drug‐eluting stents. JAMA 2007;297:2001–9.

Rates of death and heart failure in ACS decline

The management of acute coronary syndromes has evolved rapidly over the past 7 years—but has this translated into improved clinical outcomes for patients?

Using data from the GRACE (Global Registry of Acute Coronary Events), Fox et al looked at the temporal trends in the use of evidence‐based pharmacological and interventional treatments. Patient outcomes (death, congestive heart failure, pulmonary oedema, cardiogenic shock, stroke and myocardial infarction (MI)) were also examined in the 44 372 patients enrolled between 1999 and 2007.

There was an overall increase in the use of pharmacological drugs over the study period (β blockers, statins, ACE inhibitors, thienopyridines with or without percutaneous coronary intervention (PCI), glycoprotein IIb/IIIa inhibitors, low molecular weight heparin; all p<0.001). There was a 22% decline in pharmacological reperfusion, whereas primary PCI rates increased by 37%. Rates of congestive heart failure and pulmonary oedema decreased in both ST‐elevation (−9%) and non‐ST‐elevation acute coronary syndromes (−6.9%). Inhospital deaths from ST‐elevation myocardial infarction decreased by 18%, and rates of cardiogenic shock decreased by 24%. At 6‐months' follow‐up, rates of MI had decreased by 2.8% in patients with ST‐elevation, whereas rates of death had declined by 1.6% in patients with non‐ST‐elevation.

[filled triangle] Room for improvement still exists; only 85% of patients with ST‐elevation received a statin in 2006 and only 53% underwent primary PCI.

[filled triangle] Fox KAA, Steg PG, Eagle KA, et al. Decline in rates of death and heart failure in acute coronary syndromes, 1999–2006. JAMA 2007;297:1892–900.

A new role for thrombolysis?

Even after elimination of epicardial arterial occlusion, myocardial damage can still occur. Thrombus may also form in the microvasculature itself—a possible explanation for the lack of benefit shown by recent randomised controlled trials for distal protection devices on microvascular perfusion.

A pilot study of 41 patients proposed that in situ thrombus might contribute to poor myocardial perfusion after primary percutaneous coronary intervention (PPCI), and evaluated the effect of low‐dose intracoronary streptokinase after PPCI. This was a single‐centre study of patients who had their first ST‐elevation myocardial infarction (STEMI) and were due to undergo PPCI within 12 hours after symptom onset.

Patients were randomly assigned to receive intracoronary streptokinase (n = 21) after PPCI, or no additional treatment (n = 20). Two days later, cardiac catheterisation was repeated and coronary haemodynamic end points were measured using a guidewire tipped with pressure and temperature sensors. Patients with anterior myocardial infarction (14 in the streptokinase group and 16 in the control group) had echocardiographic assessment of the deceleration time of coronary diastolic flow. At 6‐months' follow‐up, angiography, technetium‐99m single‐photon emission computed tomography and echocardiography assessments were performed.

Two days after PPCI, all measures of microvascular function (means (SD)) were significantly better in the thrombolysis arm than in the control group, including coronary flow reserve (2.01 (0.57) vs 1.39 (0.31)), the index of microvascular resistance (16.29 (5.06) units vs 32.49 (11.04) units), the collateral flow index (0.08 (0.05) vs 0.17 (0.07)), mean coronary wedge pressure (10.81 (5.46) mm Hg vs 17.20 (7.93) mm Hg), systolic coronary wedge pressure (18.24 (6.07) mm Hg vs 33.80 (11.0) mm Hg) and diastolic deceleration time (828 (258) ms vs 360 (292) ms).

In light of the clinical findings, this small pilot study should pave the way for large‐scale randomised trials aimed at a multifactorial approach to minimising reperfusion injury. These should involve both non‐invasive and invasive diagnostic techniques and may highlight a new therapeutic strategy for patients with acute myocardial infarction. It should be noted that trials of facilitated PPCI, with thrombolysis given in variable doses “up‐front”, have failed to show benefit. Thus the results of this small study of streptokinase after PPCI, which showed only limited benefit at 6 months, should be treated with caution.

[filled triangle] Sezer M, Oflaz H, Goren T, et al. Intracoronary streptokinase after primary percutaneous coronary intervention. N Engl J Med 2007;356:1823–34.

[filled triangle] Piek JJ. Beyond epicardial reperfusion. N Engl J Med 2007;356:1880–2.


Valsartan shows protective effects that are supplementary to its effects on blood pressure

Angiotensin II has been implicated in the pathogenesis of coronary heart disease, stroke and heart failure. Do antihypertensive drugs that act on the renin–angiotensin–aldosterone system have additional benefits above and beyond their effects on blood pressure?

In the Jikei Heart Study, 3081 Japanese patients aged between 20 and 79 years, all of whom were undergoing conventional treatment for hypertension, coronary heart disease or stroke, were assigned either to 40–160 mg of valsartan a day (mean 75 mg/day) or to other treatment without angiotensin receptor blockers. The primary end point was a composite of cardiovascular morbidity and mortality.

After a median follow‐up of 3.1 years, the primary end point was achieved by fewer people given valsartan than in controls (92 vs 149; p = 0.0002), attributable to fewer strokes/transient ischaemic attacks (29 vs 48; p = 0.028), less angina pectoris (19 vs 53; p<0.0001), and less heart failure (19 vs 3; p = 0.029). Mortality or tolerability did not differ between the groups.

Asian patients have traditionally been under‐represented in clinical trials, including those of angiotensin receptor blockers. Interestingly, both treatment groups in this trial achieved good blood pressure control, suggesting that the possible additional benefits of angiotensin receptor blockers shown might be due to their effects on the renin–angiotensin–aldosterone system.

[filled triangle] Mochizuki S, Dahlof B, Shimizu M, et al. Valsartan in a Japanese population with hypertension and other cardiovascular disease (Jikei Heart Study): a randomised, open‐label, blinded endpoint morbidity‐mortality study. Lancet 2007;369:1431–9.

Levosimendan: helping to SURVIVE heart failure?

Levosimendan increases the sensitivity of the heart to calcium, thus increasing cardiac contractility; might it be useful in the treatment of acute decompensated heart failure?

In the SURVIVE (Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support) trial, 1327 patients admitted to hospital with acute decompensated heart failure who required inotropic support were randomised to intravenous levosimendan (n = 664) or dobutamine (n = 663). The main outcome measure was all‐cause mortality at 180 days.

Twenty‐six per cent of patients in the levosimendan group and 28% of patients in the dobutamine group died at 180 days (p = 0.40). The levosimendan group exhibited greater decreases in B‐type natriuretic peptide level at 24 hours, which persisted through 5 days, than the dobutamine group (p<0.001). None of the secondary end points (all‐cause mortality at 31 days, number of days alive and out of hospital, patient global assessment, patient assessment of dyspnoea at 24 hours, and cardiovascular mortality at 180 days) reached statistical significance. Although there was a higher incidence of cardiac failure in the dobutamine group, atrial fibrillation, hypokalaemia and headache were all more common in the levosimendan group.

Therefore although levosimendan initially reduced plasma B‐type natriuretic peptide levels in the levosimendan group, it did not affect mortality at 180 days or any secondary outcomes.

[filled triangle] Mebazaa A, Nieminen MS, Packer M, et al. Levosimendan vs dobutamine for patients with acute decompensated heart failure. The SURVIVE randomized trial. JAMA 2007;297:1883–91.

Antiretroviral drugs and cardiovascular risk

Soon after combination therapy with antiretroviral agents was introduced in HIV, reports appeared of acute myocardial infarction (MI) and premature atherosclerotic disease in young patients receiving this treatment. More recently, several prospective studies have started to clarify the complex interactions between the various antiretroviral agents, HIV infection and cardiovascular risk.

The Data Collection on Adverse Events of Anti‐HIV Drugs (DAD) study, was an international collaboration following up 23 437 HIV‐1 infected patients at 188 clinics in 21 countries. Patients were followed up prospectively for a median of 4.5 years during their regular visits to outpatient clinics. Three hundred and forty‐five patients had an MI during 94 469 person‐years of observation. After adjusting for cardiovascular risk factors (excluding lipids), patients receiving protease inhibitors had an increase in the risk of MI of 16% a year (p<0.001) compared with only 5% a year (p = 0.17) among patients receiving non‐nucleoside reverse transcriptase inhibitors. Adjusting for lipid levels, diabetes mellitus and hypertension, reduced the relative risk of protease inhibitors to 10% (p = 0.002) and for non‐nucleoside reverse transcriptase inhibitors to 0% (p = 0.92).

The authors concluded that use of protease inhibitors was associated with an increased risk of MI, partly explained by dyslipidaemia and that no such association was seen with non‐nucleoside reverse transcriptase inhibitors. However, uncontrolled viraemia is a much greater risk factor for cardiovascular death than the metabolic changes caused by antiretroviral drug treatment. It should also be noted that increasing age remains a risk factor for cardiovascular disease and therefore timely attention to modifiable risk factors is prudent.

Protease inhibitor treatment may modestly increase cardiovascular risk, but further studies will be necessary to understand fully the significance of this observation and also identify which subclasses of protease inhibitors are responsible.

[filled triangle] The DAD Study Group. Class of antiretroviral drugs and the risk of myocardial infarction. N Engl J Med 2007;356:1723–35.

[filled triangle] Stein JH. Cardiovascular risks of antiretroviral therapy. N Engl J Med 2007;356:1773–5.

Journals scanned

American Journal of Medicine; American Journal of Physiology: Heart and Circulatory Physiology; Annals of Emergency Medicine; Annals of Thoracic Surgery; Archives of Internal Medicine; BMJ; Chest; European Journal of Cardiothoracic Surgery; Lancet; JAMA; Journal of Clinical Investigation; Journal of Diabetes and its Complications; Journal of Immunology; Journal of Thoracic and Cardiovascular Surgery; Nature Medicine; New England Journal of Medicine; Pharmacoeconomics; Thorax


Dr Alistair Lindsay, Dr Katie Qureshi

Articles from Heart are provided here courtesy of BMJ Group