Keeping pace with post-MI pharmacological agents

It is difficult to comprehend the great advances made in the treatment of the patient following an acute myocardial infarction (MI) over the past 50 years. The era of routine anti-arrhythmic drug use and long-term bed rest has now been replaced by a combination of invasive coronary interventions and the implementation of pharmacological agents, which have been shown in large randomised controlled trials to significantly lower mortality among post-MI patients. The aim of this review is to provide an overview of the major agents which are implemented in clinical practice.

Antiplatelet therapy

Although aspirin has been in existence as a medicinal agent for over 100 years, its use in patients following an acute MI was first studied in the early 1970s. It is now well established that aspirin therapy results in a significant reduction in the risk of subsequent MI, stroke and vascular death among a wide range of patients who have survived an occlusive cardiovascular event. Platelet adhesion, activation and aggregation are central to thrombus formation, which follows atherosclerotic plaque disruption and may result in an acute coronary syndrome (ACS). Aspirin exerts its antiplatelet effect by inhibiting thromboxane A2 production, which plays the key role in the platelet aggregation pathway. 

The Antithrombotic Trialists’ Collaboration analysed the results of 195 randomised trials of antiplatelet therapy, principally with aspirin, among more than 135,000 high-risk patients with prior evidence of cardiovascular disease (CVD), including prior MI.¹ This concluded that aspirin therapy significantly reduced the relative risk of subsequent vascular events (non-fatal MI, non-fatal stroke and vascular death) by approximately 22%. There was no difference in the efficacy between doses of 75-150mg/day (low-dose aspirin) and 160-325mg/day (medium-dose aspirin).

Clopidogrel is a thienopyridine which exerts its effects by inhibiting ADP receptors (P2Y12 subtype). The blockade of these receptors inhibits platelet aggregation by blocking activation of the glycoprotein IIb/IIIa pathway. It is used in combination with aspirin for 12 months following both ST-elevation MI (STEMI)² and non-ST elevation MI (NSTEMI).³ Clopidogrel should also be given along with aspirin in patients who underwent percutaneous coronary intervention (PCI [coronary stenting]) after an ACS, for a period of at least one year.^2,3 It is recommended that antiplatelet therapy (aspirin and clopidogrel) should be given for three months after bare metal stents (BMS) and for 12 months after drug-eluting stents (DES). 

Clopidogrel monotherapy is an alternative when aspirin is contraindicated.⁴ Both aspirin and clopidogrel increase the bleeding risk but the cardiovascular benefit has always outweighed this risk in numerous studies. In a 2011 meta-analysis, low doses of aspirin alone decreased the risk for all-cause mortality, increased the risk for GI bleeding which further increased with accompanying use of clopidogrel and anticoagulant therapies, but decreased in patients who took proton pump inhibitors (PPIs).⁵

Prasugrel and ticagrelor are two important emerging antiplatelet agents which are being studied in the setting of acute MI, particularly in those requiring PCI. Prasugrel has a more rapid onset of action and is able to achieve higher degrees of platelet inhibition than clopidogrel, while having a comparable rate of significant bleeding.

 The efficacy of prasugrel was compared to clopidogrel in the TRITON-TIMI 38 trial, which found that the primary efficacy endpoint of cardiovascular death, non-fatal MI or non-fatal stroke occurred significantly less often in patients treated with prasugrel, driven primarily by a significant reduction in non-fatal MI.⁶ This benefit was found in patients with either procedure-related or non-procedure-related MIs and was seen irrespective of MI size or timing.⁶ Also the rate of definite or probable stent thrombosis was significantly reduced in the prasugrel group.

Ticagrelor differs from the thienopyridines (clopidogrel and prasugrel) in that it binds reversibly rather than irreversibly with the P2Y12 platelet receptor and has a more rapid onset of action than clopidogrel. Similar to prasugrel, treatment with ticagrelor leads to more intense platelet inhibition than clopidogrel. Ticagrelor was compared to clopidogrel in ACS patients in the PLATO trial and it was found that in patients who have an ACS with or without ST-segment elevation, treatment with ticagrelor as compared with clopidogrel significantly reduced the rate of death from vascular causes, MI or stroke without an increase in the rate of overall major bleeding but with an increase in the rate of non-procedure-related bleeding.⁷

Lipid-lowering drugs

All patients following an acute MI should receive long-term lipid-lowering therapy with a statin. Statins in all patients, in the absence of contraindications, irrespective of cholesterol levels, should be initiated as soon as possible. The targets established by the Fourth Joint Task Force of the ESC and other societies in patients after infarction are: for total cholesterol of 4.5mmol/L (175mg/dL) with an option of 4.0mmol/L (155mg/dL) if feasible; and for low-density lipoprotein (LDL) cholesterol of 2.5mmol/L (100mg/dL) with an option of 2.0mmol/L (80mg/dL) if feasible.² In addition, all patients should receive dietary advice. As well as reducing cholesterol levels, statins may exert a variety of pleiotropic effects which provide additional benefit in the setting of an ACS. These effects include plaque stabilisation, reduction of inflammation by lowering C-reactive protein levels (CRP), reversal of endothelial dysfunction and decreased thrombogenicity.

The PROVE IT-TIMI 22 trial concluded that, among patients who have recently had an ACS, an intensive lipid-lowering statin regimen (in this case atorvastatin 80mg/day) provided greater protection against death or major cardiovascular events than a standard regimen (pravastatin 40mg/day).⁸ Rosuvastatin is another commonly used statin, which is also found to be effective in raising high-density lipoprotein (HDL) and lowering C-reactive protein (CRP) levels.

Adverse reactions occur less frequently with the statins than with most other classes of lipid-lowering agents. Hepatic dysfunction has been a source of concern, however the actual risk appears to be very small. Myopathy remains an important side-effect but muscle injury is uncommon with statin therapy alone, with a frequency of 2-11% for myalgia, 0.5% for myositis and less than 0.1% for rhabdomyolysis. Hydrophilic statins (pravastatin and rosuvastatin) appear to have less intrinsic muscle toxicity than other statins.⁹ Evaluation of the response to statins after an ACS should be deferred for two months, since acute phase responses can transiently lower LDL by 40-50% and thus, in some patients, cause spuriously normal-appearing levels.

Among the non-statin agents, nicotinic acid (niacin) has some of the best evidence suggesting mortality benefits in secondary prevention of coronary heart disease. It is found to be effective in increasing HDL concentrations and reducing the lipoprotein(a) and LDL levels.¹⁰ Flushing, pruritus, paraesthesias and nausea are common side-effects but pre-treatment with aspirin (300-650mg) or ibuprofen (200mg) prior to dosing and nocturnal use can minimise flushing.

For patients requiring combined statin-fibrate therapy (for hypertriglyceridaemia), fenofibrate is the fibrate of choice because it does not result in increased blood levels of statins thereby reducing the risk of associated muscle toxicity.

Ezetimibe is a cholesterol absorption inhibitor. Although it reduces LDL, including when used in combination with a statin, there is no convincing evidence that it improves clinical outcomes beyond treatment with a statin alone.

Beta-adrenergic blockers

Several trials have demonstrated that ß-adrenergic blockers reduce mortality and re-infarction by 20-25% in those who have recovered from an infarction and recommend that they should be used indefinitely unless contraindicated. ß-blockers are regarded as an essential component in management of patients with MI due to their numerous benefits, such as decreased oxygen demand due to the reductions in heart rate, blood pressure and contractility, and the consequent relief of ischaemic chest pain, decreased risk of ventricular fibrillation and automaticity, improved coronary diastolic perfusion and reduction in remodelling.^11,12

A meta-analysis of 82 randomised trials provides strong evidence for long-term use of ß-blockers to reduce morbidity and mortality after STEMI even if ACE inhibitors are co-administered.¹³ The significant mortality reductions observed with ß-blockers in heart failure, in general, further support the use of these agents after MI.

A selective ß-1 blocker, such as metoprolol, atenolol or bisoprolol, is preferred; the dose titrated according to the response. The efficacy of carvedilol (non-selective ß-blocker/‮#‬‭\‬-1 blocker) has been supported by significant trials, especially in the setting of chronic heart failure secondary to CVD. Major contraindications to ß-blockers include active bronchospasm; severe bradycardia; heart block greater than first degree (unless the patient has a permanent pacemaker); pulmonary oedema; and hypotension, with or without shock. Such patients should be re-evaluated for ß-blocker candidacy after they stabilise.

Renin-angiotensin system (RAS) and aldosterone system blockade

ACE inhibitors and angiotensin receptor blockers (ARBs) are well established in secondary prevention, especially in patients with reduced LV function.

ACE inhibitors

The deleterious effects of pathology affecting the RAS lie in the imbalance of angiotensin-2 and bradykinin levels. ACE inhibitors and ARBs improve this balance, which is the basis of their beneficial effects, varying from antihypertensive, cardioprotective to anti-atherosclerotic effects.

In the Acute Infarction Ramipril Efficacy (AIRE) trial,¹⁴ the ACE inhibitor ramipril was given within two to nine days of an MI, significantly decreasing mortality over a mean period of 15 months. The 2008 ESC guidelines on the management of acute MI in patients presenting with persistent ST-segment elevation state that use of ACE inhibitors should be considered in all patients with atherosclerosis but, given the relatively modest effect, their long-term use cannot be considered to be mandatory in post-STEMI patients who are normotensive, without heart failure or compromised systolic LV function. There is not enough evidence to support the use of ACE inhibitors in NSTEMI and unstable angina and, therefore, in patients at lower risk (a normal left ventricular ejection fraction [LVEF], well-controlled cardiovascular risk factors and performance of revascularisation) the benefits of long-term therapy should be weighed against the potential burdens (side-effects, complicated medical regimens or financial concerns).¹⁵

Angiotensin receptor blockers 

ARBs act within the RAS by blocking the angiotensin II AT1 receptor resulting in a series of beneficial cardiovascular effects including reduced vasopressin and aldosterone secretion as well as reducing blood pressure.

Only one study conducted in 2003 specifically compared ARB (candesartan in low dose) versus placebo in post-MI patients without chronic heart failure. This concluded that treatment with candesartan was associated with a reduction in the primary endpoint, which was the combination of revascularisation, non-fatal MI and cardiovascular mortality.¹⁵ There were no studies found which specifically examined the efficacy of treatment with an ARB in asymptomatic patients with left ventricular dysfunction.

In comparing ARBs to ACE inhibitors, the OPTIMAAL trial with losartan (50mg) failed to show superiority or non-inferiority over captopril (50mg three times daily).¹⁶

 The VALIANT trial, on the other hand, compared valsartan alone (160mg twice daily), full-dose captopril (50mg three times daily) and both (80mg twice daily and 50mg three times daily). It did not show any difference in mortality but proved that discontinuations were more frequent in the groups receiving captopril. The study concluded that valsartan in dosages as used in the trial represents an alternative to ACE inhibitors in patients who do not tolerate ACE inhibitors and have clinical signs of heart failure and/or an EF 40%.¹⁷

The recommendation now is that ARB use is reserved for patients who are intolerant to ACE inhibitors, most commonly due to cough. The combination of both ACE inhibitors and ARBs is not recommended.³

Aldosterone antagonists

Aldosterone antagonists, namely eplerenone, have been shown to reduce cardiovascular mortality after MI in patients with reduced LV function (LVEF < 35%), even in only mildly symptomatic patients.¹⁸ Results of the EPHESUS trial suggest that aldosterone blockade may be considered for post-STEMI patients with an EF 40% and heart failure or diabetes provided that creatinine is < 2.5mg/dL in men and < 2.0mg/dL in women, and potassium is < 5.0mEq/L.¹⁹

Direct renin inhibitors

A recent trial published in December 2010²⁰ concluded that adding the direct renin inhibitor aliskiren to standard therapy, including an inhibitor of the renin-angiotensin-aldosterone axis, in high-risk post-MI patients did not result in further attenuation of left ventricular remodelling and was associated with more adverse effects, suggesting no additional benefit of dual renin-angiotensin-aldosterone axis blockade with aliskiren.

Anti-anginals

Nitrates

The majority of evidence supporting use of nitrates was in the context of acute MIs and they remain the first-line medication in angina pectoris. They exert their anti-anginal effect by causing direct coronary vessel dilatation and by reducing venous return and left ventricular end-diastolic pressure, hence, they lower myocardial oxygen demand and consequently improve blood flow to the sub-endocardium. This results in rapid symptom relief from angina episodes. Long-term use of nitrates, however, remains controversial as there has been no solid evidence to prove that they have any positive impact on mortality. A trial published in the Japanese Circulation Journal in 1996²¹ concluded that long-term treatment with nitrates increased cardiac events in patients with healed MI.

The fourth Internal Study of Infarct Survival (ISIS-4),²² which studied benefits of nitroglycerin as well as captopril, and intravenous magnesium sulphate in patients presenting with suspected acute MI, concluded that there was no significant reduction in mortality, neither at 35 days nor at 12 months follow-up, to indicate any late survival advantage. Critics of ISIS-4 have cited the low dose of mononitrate which, at least in some studies, has been shown to be relatively ineffective.²³

It must be noted that nitrates are contraindicated in patients with right ventricular infarcts and hypotension.

Nicorandil

Nicorandil is an arterial and venous dilator and improves coronary blood flow due to potassium channel opening and nitrate effect. The NICE 2007 guidelines stated that there is no significant reduction in coronary heart disease mortality or non-fatal MI in patients treated with nicorandil. 

The IONA trial²⁴ evaluated the impact of nicorandil on patients with chronic stable angina receiving other standard therapies (anti-platelet drugs, ß-blockers, statins, ACE inhibitors and calcium channel blockers). 

It showed a significant improvement in outcome due to a reduction in major coronary events by anti-anginal therapy with nicorandil in patients with stable angina. 

However, IONA was an outcome study and provided little information regarding the effects of nicorandil on angina symptoms. There was little difference in worsening of anginal symptoms in the nicorandil group as compared to placebo.

Ivabradine

Ivabradine, one of the recently introduced drugs in the field of ACS, has the potential advantage of reducing heart rate without lowering blood pressure. It exerts its effect by acting directly on the sinus pacemaker. A placebo-controlled trial in 2003²⁵ concluded that ivabradine produces dose-dependent improvements in exercise tolerance and time to development of ischaemia during exercise. These results suggest that ivabradine, representing a novel class of anti-anginal drugs, is effective and safe during three months of use. However, it did suggest that longer-term safety required further assessment.

Ivabradine, by selectively controlling heart rate, seems to be a valuable addition in management of heart failure complicating acute MI in reducing in-hospital events. It needs to be validated in further randomised studies.

Another trial conducted in 2005²⁶ stated that ivabradine is as effective as atenolol in patients with stable angina. The recent ESC guidelines in 2011 suggested use of ivabradine in patients with contraindications to ß-blockers in the context of secondary prevention of MI.³

Newer agents

Stem cell therapy

Newer forms of therapy such as transplantation of haematopoietic or bone marrow mesenchymal stem cells are being evaluated. One pilot study in 2006²⁷ concluded that intracoronary administration of bone marrow-derived progenitor cells (BMC) is associated with improved recovery of left ventricular contractile function in patients with acute MI. 

Large-scale studies are warranted to examine the potential effects of progenitor-cell administration on morbidity and mortality. Long-term benefits were not as promising as the short-term benefit of therapy but this has yet to be clarified.

Therapeutic angiogenesis

The administration of angiogenic growth factors such as fibroblast growth factor (FGF), platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) to stimulate new vessel formation to provide effective blood supply to an area of myocardium affected by coronary arterial occlusion is considered to be an area to be explored, particularly in patients in whom PCI or coronary artery bypass surgery seem to be unfeasible options. To date there has been no proven benefit to suggest this as a recommendation but it is still a field to be explored by further studies.

Omega-3 fatty acids

The administration of omega-3 fatty acids for secondary prevention of MIs has generated a lot of debate and has been the subject of trials both supporting and opposing its benefit. A limited number of studies suggest that fish oil consumption may modestly reduce the chronic progression of stable arterial plaque.²⁸ In contrast, appreciable effects on thrombosis are not seen until very high levels of supplementation (> 5-10/day) are reached.²⁹ A trial in August 2010³⁰ concluded that low-dose supplementation with EPA-DHA or ALA did not significantly reduce the rate of major cardiovascular events among patients who had had a MI and who were receiving state-of-the-art antihypertensive, antithrombotic and lipid-modifying therapy. 

Another Norwegian trial concluded that among Norwegian patients with CAD consuming relatively high amounts of n-3 LCPUFAs and fish, there were no significant trends toward a reduced risk of coronary events or mortality with increasing intakes.³¹ The GISSI Prevenzione trial, a randomised study, showed that 1g daily of fish oil on top of a Mediterranean diet significantly reduced total and cardiovascular mortality.³²

A meta-analysis, including Prevenzione, showed no effect on mortality or cardiovascular events and no evidence that the source or dose affect outcome.³³ The role of omega-3 fatty acids in secondary prevention of MI is yet to be properly understood. The NICE guidelines 2007 recommend an intake of 7g of omega-3 fatty acids per week.

Conclusion

Since the 1980s, management of MI and post-MI care has been constantly evolving to an extent that left many practitioners feeling out of pace in keeping up with it, especially with new drugs flooding the market at very short intervals. 

The developments came with the advances in understanding the pathophysiology underlying the acute coronary syndromes, better modalities of diagnosis and follow-up as well as the advances made in the interventional aspect of management. All of these dictated constant changes in the guidelines to offer best practice and improved outcomes in terms of both morbidity and mortality. Despite all the advances angina remains to have a population prevalence of approximately 5-6%, which is why primary prevention remains the cornerstone of proper management. Early identification of patients with risk factors is, of course, key in reaching that goal.

Despite the constant updates in management of ACS, ß-blockers, antiplatelets, statins and ACE inhibitors have remained as first line on which other modalities may be added. Though we now have clear guidelines in the management of ACS, it is worthwhile to note that each patient should be assessed individually as to what is most appropriate for them given the many factors surrounding their presentation and diagnosis. 

Physicians should constantly assess their patients’ medications and their need for them. Many patients who are seen in the first instance in primary or secondary health service and, due to the high index of suspicion, are managed as ACS, are started on their secondary prevention but would remain on these medications despite the subsequent investigations having proven negative for ACS. As much as we want all at-risk patients to be on the right medications it should be remembered that medications are not risk-free and should only be used when their benefit outweighs their risks. Pharmacological management for secondary prevention of ACS is only part of the package that should be offered to patients. The crucial importance of non-pharmacological interventions, including diet, exercise and cardiac rehabilitation, should well be stressed to patients to offer optimum level of care.

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