Recent advances: Cardiology

Platelet glycoprotein IIb/IIIa inhibition

Interest in the role of platelets in forming the thrombus has led to identification of the platelet surface glycoprotein IIb/IIIa complex, which, when activated by exposure to ADP or thrombin, binds fibrinogen and links platelets into large aggregates.1 Inhibitors of this complex, a member of the integrin family of adhesion receptors mediating the final common pathway in platelet aggregation, have been evaluated in the acute ischaemic syndromes and after coronary angioplasty. One such inhibitor is a mouse monoclonal antibody, known as 7E3 or abciximab. When given to patients with evolving acute myocardial infarction or unstable angina who are undergoing coronary angioplasty, this agent has produced remarkable reductions in acute myocardial infarction and need for urgent revascularisation in the 30 days after the procedure and beyond (table 1).2-5

The effects of other inhibitors are less conclusive. Intravenous treatment with lamifiban has been tried with uncertain results (PARADIGM trial6), but preliminary data on tirofiban from the PRISM trials are promising (P Theroux, data presented at the 1997 American College of Cardiology meeting). Other agents in this class are being evaluated, both orally and intravenously.

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Hirudin

Thrombin plays a central role in coronary artery thrombosis, promoting platelet aggregation, a process enhanced by a positive feedback loop, and catalysing cross linkage of the fibrin clot.7 Although heparin remains the mainstay of antithrombin treatment, several other agents have been tested in patients with acute myocardial infarction and unstable angina. Hirudin, a direct thrombin inhibitor derived from the saliva of the medicinal leech (Hirudo medicinalis), shows some promise if safe and effective doses can be devised. Early trials showed that hirudin, at doses that were subsequently regarded as being too high, led to excess spontaneous intracranial bleeding (GUSTO IIa)8 or other serious haemorrhage (TIMI 9A).9 The results of GUSTO IIb, a continuation of GUSTO IIa with a lower dose of hirudin, were mixed and did not suggest a benefit at 30 days.10

Whether hirudin truly has no advantage over heparin or the dose used in GUSTO IIb was too low or other variables are involved is being evaluated in the OASIS trial. In an OASIS pilot study, which compared two doses of hirudin (both higher than that in GUSTO IIb) with heparin, the effects on cardiovascular death, new acute myocardial infarction, or refractory angina at seven days were encouraging.11 However, when the study treatment was stopped the number of ischaemic events increased in the group receiving the lower dose of hirudin after about 24 hours and in the group receiving the higher dose after about five days. Examination of the clotting parameters suggested the presence of a rebound phenomenon, which could perhaps be avoided with continued anticoagulation treatment.11 The OASIS trial therefore uses a slightly higher dose of hirudin than in GUSTO IIb (or standard heparin), and before this treatment is stopped patients are randomised to oral warfarin anticoagulation treatment.

If it is proved safe and efficacious, the continued suppression of the coagulation parameters, plus antiplatelet treatment with the glycoprotein IIb/IIIa inhibitors, may represent a clear advantage over the current treatment with aspirin, with or without heparin.

Primary coronary angioplasty

An increasingly common practice in some centres is to use primary coronary angioplasty in acute myocardial infarction. This is driven by the generally accepted concept of the “open artery hypothesis,” which suggests that early opening of the artery responsible or related to the region of myocardial necrosis reduces the risks of mortality and morbidity. In primary coronary angioplasty, the patient is brought directly to the cardiac catheterisation laboratory for coronary angioplasty without benefit of thrombolysis.12-14 Two moderately sized trials, both enrolling over 300 patients with acute myocardial infarction, have reported significant reductions in short term mortality. 13 14 A systematic overview, conducted on 8496 patients in seven small trials of primary coronary angioplasty and in 16 trials in which coronary angioplasty was administered after thrombolysis, concluded that primary coronary angioplasty may be more beneficial than thrombolysis in some, but not all, circumstances.12 In practice, primary coronary angioplasty is of limited application since the procedure can be carried out only in centres where the necessary staff and equipment are available 24 hours a day.

Platelet IIb/IIIa inhibition

This has been discussed above. One agent, abciximab, has been clearly shown to be beneficial in a randomised, double blind trial of 2099 patients undergoing coronary angioplasty or atherectomy for severe unstable angina, evolving acute myocardial infarction, or high risk coronary morphology. 2 3 Results from this and other trials are consistently encouraging (table 1) and suggest that platelet IIb/IIIa inhibition can prevent abrupt closure after coronary angioplasty and reduce the need for subsequent coronary vascularisation. The disadvantage is that there is a small excess risk of serious bleeding with this treatment, and there may be other adverse effects as yet unknown.

Intracoronary stenting

This procedure is a high technology innovation in which a balloon-expandable, stainless steel tube is implanted at the site of a coronary lesion. The stent was developed initially to treat acute or threatened vessel closure after coronary angioplasty. Several studies have shown that stenting is feasible in most cases, and this procedure has resulted in impressive reductions in serious complications with coronary angioplasty. 15 16 Primary stenting in conjunction with coronary angioplasty is now being increasingly used to prevent restenosis in patients who do not have acute or threatened vessel closure, and this has been boosted by encouraging results from two randomised trials (table 2). 17 18

Antiplatelet therapy seems to offer greater efficacy and safety in preventing the major problems of stent thrombosis and occlusion than the alternative treatment with intensive anticoagulation.19 Similar conclusions can be drawn from the EPIC trial. 2 3 The new, heparin bonded stent is being tested in the observational BENESTENT II study and the randomised TOSCA trial.

Despite the relative lack of information on short term efficacy and long term outcomes, stents are increasingly being used. Although this practice seems to reduce the need for bypass surgery, the long term consequences are not clear.

Lipid lowering treatment

With the introduction of a new class of highly effective and easily tolerated drugs, the hydroxymethyl glutaryl coenzyme A reductase inhibitors, lipid lowering treatment in secondary and, to some extent, primary prevention is becoming more practical. Although there is a clear recognition of the central role of elevated serum cholesterol concentrations in the development of coronary atherosclerosis, until recently cholesterol lowering clinical trials that showed beneficial reductions in cardiovascular events and mortality had been exclusively carried out in high risk patients with raised cholesterol levels. Little information has been available on the effects of cholesterol lowering treatment in patients with normal or mildly elevated levels.

Three secondary prevention trials20-22 and a primary prevention trial of high risk subjects23 have addressed these issues recently (table 3). The secondary prevention 4S trial showed, for the first time, that cholesterol lowering treatment does reduce total, as well as cardiac, mortality.20 The CARE21 and Post-CABG trials22 further showed the safety and efficacy of reducing total cholesterol and low density lipoprotein cholesterol concentrations to levels that had been regarded by some as potentially harmful because of the so called J curve phenomenon. Altogether, data from these trials conclusively confirm that long term cholesterol lowering is safe and beneficial, even in patients with normal cholesterol concentrations.

Other treatments

Equally intriguing, but not proved conclusively, is the anti-ischaemic role of angiotensin converting enzyme inhibitors. These drugs are known to have several potentially beneficial protective effects on cardiac and vascular function, but whether these will translate into clinically useful effects is only now being tested in several large randomised trials such as the HOPE trial. Another potentially useful approach, again studied in the HOPE trial, is anti-oxidant therapy (vitamin E), which is based on the pathophysiological concept of lipid oxidation and atherogenesis.

Digitalis

Although the clinical use of digitalis is long established, its safety and efficacy in reducing mortality were only recently addressed in a large (7788 patient) placebo controlled, randomised clinical trial by the Digitalis Investigation Group (DIG) Investigators.24 Mortality did not differ between the groups given active treatment and placebo (34.8% v 35.1%). There was, however, a slightly decreased risk of death attributed to worsening heart failure in the digoxin treated group compared with the placebo group (11.6% v 13.2%, P=0.06) and fewer hospitalisations due to heart failure in the digoxin group (26.8% v 34.7%, P<0.001). An ancillary trial of patients with presumed diastolic dysfunction gave results consistent with those of the main trial for the primary combined endpoint of death or hospitalisation due to worsening heart failure.24

While the DIG trial may be disappointing to some because of the lack of a clear difference, the findings are important. They confirm that there are no long term safety concerns when digitalis is used to improve exercise tolerance and quality of life. It also reduces hospitalisation due to worsening heart failure. Symptomatic patients with preserved left ventricular function derive benefits similar to those experienced by patients with poor systolic function.

Other positive inotropic agents

Several other positive inotropic drugs have been tested in clinical trials recently, but practically all of these had to be stopped prematurely because of excess mortality in the groups of patients receiving the active agents. Unlike digitalis, these drugs—including milrinone,25 enoximone,26 and ibopamine27—demonstrate positive inotropism through stimulation of adrenergic receptors or the post-receptor pathway, but they are associated with increased frequency of ventricular arrhythmias and excess mortality.

Neurohormonal blockade

The concept of neurohormonal blockade in congestive cardiac failure, associated with activation of the sympathetic and renin-angiotensin neurohormonal systems, is important both prognostically and therapeutically. Angiotensin converting enzyme inhibition, by blocking the effects of renin-angiotensin activation, has been found to be highly effective in reducing mortality in congestive heart failure and reducing disease progression. 28 29 Drugs that selectively block the effects of angiotensin II at the receptor levels (A-II receptor antagonists) have been developed, and some are being tested. Preliminary data on one such drug, losartan, suggest that it or this class of drugs can improve symptoms and perhaps reduce mortality in congestive heart failure, as suggested by the results of the ELITE study.30 Other studies are ongoing.

β blockade

Blockade of the chronically activated sympathetic system in congestive heart failure is the basis for the use of β blockers, despite the traditional view that β blockers are contraindicated in this condition. Again, preliminary data are promising. 31 32 Although sympathetic activity is essential in acute heart failure in order to maintain adequate cardiac output and perfusion pressure of the vital organs, chronic sympathetic stimulation, as in congestive heart failure, produces deleterious effects. While small studies of β blockade in congestive heart failure have suggested beneficial results, 31 32 the development of a new β blocker with α₁ blocking effect, carvedilol, has led to a greater impetus in testing and using β blockers in congestive heart failure.33 The US Carvedilol Heart Failure Group has reported the experience of 1094 patients with congestive heart failure who were enrolled in a double blind, placebo controlled, stratified study: the group treated with carvedilol showed reductions in mortality at 6 months compared with the placebo group (3.2% v 7.8%, P<0.001), in hospitalisation for cardiovascular causes (P=0.036), and in the combined endpoint of hospitalisation or death (P<0.001).33

Although promising, the number of deaths is small because of the moderate size and short follow up of the trial. Thus, there is still a degree of uncertainty that needs further study. Should further evidence confirm these findings, however, it will prompt acceptance of the concept of β blockade in congestive heart failure and encourage the use of β blockers. In practice, care is needed to start treatment with β blockers at low doses and gradually titrate the dose upwards in order to avoid sudden haemodynamic shifts and symptomatic deterioration caused by the abrupt β blocking effects on heart rate and blood pressure. This deterioration may occur even in those patients who will eventually benefit from this treatment.

Amiodarone

Although amiodarone is generally accepted as highly effective in reducing risks of sudden cardiac death in patients at very high risk, routine use of this drug in subsets of patients at high risk after acute myocardial infarction or with congestive heart failure is being debated. Meta-analyses of data from small clinical trials of amiodarone in such patients suggested a beneficial effect,34 but data from two recent trials of patients with congestive heart failure were conflicting (for details see table on BMJ website at www.bmj.com). 35 36 It was hoped that the Canadian (CAMIAT)37 and European (EMIAT)38 trials of amiodarone in patients at high risk after acute myocardial infarction could settle the uncertainty. While both studies showed that amiodarone significantly reduced arrhythmic deaths or non-fatal arrhythmic events, they provided no conclusive data on overall or cardiac mortality (for details see table on BMJ website at www.bmj.com).

Implantable cardioverter defibrillators

These devices deliver an electric shock to the heart when ventricular fibrillation or tachycardia occurs. They are increasingly being touted as efficacious and cost effective initial treatment for preventing sudden death in patients with malignant ventricular tachyarrhythmias.39 Although much of the evidence for this benefit comes from uncontrolled observational studies, some trial data are now available. Preliminary data from the small randomised CASH and NCES trials are promising. 39 40 The MADIT study also showed that patients treated with implantable cardioverter defibrillators had better survival rates than those treated conventionally with drugs.41 While the preliminary data are promising, we must await results from the recently terminated AVID trial and the ongoing CIDS, MUSTT, and other trials for further answers.