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National Collaborating Centre for Primary Care (UK). Post Myocardial Infarction: Secondary Prevention in Primary and Secondary Care for Patients Following a Myocardial Infarction [Internet]. London: Royal College of General Practitioners (UK); 2007 May. (NICE Clinical Guidelines, No. 48.)

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Post Myocardial Infarction: Secondary Prevention in Primary and Secondary Care for Patients Following a Myocardial Infarction [Internet].

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6Drug Therapy

6.1. Recommendations for Drug Therapy

6.1.1. Overall drug therapy recommendation

6.1.1.1All patients who have had an acute MI should be offered treatment with a combination of the following drugs (Grade A):
  • ACE (angiotensin-converting enzyme) inhibitor
  • beta-blocker
  • statin.

6.1.2. ACE inhibitors recommendations

Hyperlink to the related evidence statements

6.1.2.1Early after presenting with an acute MI, all patients should be offered an ACE inhibitor (Grade A).
6.1.2.2ACE inhibitor therapy should be initiated at the appropriate dose, and titrated upwards at short intervals (for example every 1 to 2 weeks) until the maximum tolerated or target dose is reached (GPP).
6.1.2.3Assessment of left ventricular function is recommended in all patients who have had an MI (GPP).
6.1.2.4After an MI, all patients with preserved left ventricular function or with left ventricular systolic dysfunction should continue treatment with an ACE inhibitor indefinitely, whether or not they have symptoms of heart failure (Grade A).
6.1.2.5Routine prescription of angiotensin receptor blockers (ARBs) after an acute MI is not recommended (GPP).
6.1.2.6For patients after an acute MI who have had to discontinue an ACE inhibitor because of intolerance (for example because of cough) or allergy, an ARB should be substituted (Grade A).
6.1.2.7Combined treatment with an ACE inhibitor and an ARB is not recommended for routine use in patients early after an acute MI with heart failure and/or left ventricular systolic dysfunction (Grade A).
6.1.2.8In patients with a proven MI in the past (more than 1 year ago) and with heart failure and left ventricular systolic dysfunction, ACE inhibitor and ARB treatment should be in line with ‘Chronic heart failure. NICE clinical guideline 5’ (Grade A).
6.1.2.9In patients with a proven MI in the past and with left ventricular systolic dysfunction, who are asymptomatic, ACE inhibitor treatment should be offered and the dose titrated upwards, as tolerated, to the effective clinical dose for patients with heart failure and left ventricular systolic dysfunction (Grade A).
6.1.2.10In patients with a proven MI in the past without heart failure and with preserved left ventricular function, ACE inhibitor treatment should be offered and the dose titrated upwards, as tolerated, to the effective clinical dose (Grade A).
6.1.2.11In patients with a proven MI in the past with left ventricular systolic dysfunction, who are asymptomatic and who have had to discontinue an ACE inhibitor because of intolerance (for example because of cough) or allergy, an ARB should be substituted (Grade A).
6.1.2.12Renal function, serum electrolytes and blood pressure should be measured before starting an ACE inhibitor or ARB and again within 1 or 2 weeks of starting treatment. Patients should be monitored as appropriate as the dose is titrated upwards, until the maximum tolerated or target dose is reached, and then at least annually. More frequent monitoring may be needed in patients who are at increased risk of deterioration in renal function. Patients with chronic heart failure should be monitored in line with ‘Chronic heart failure. NICE clinical guideline 5’ (GPP).

6.1.3. Anti-platelet recommendations

Hyperlink to the related evidence statements

6.1.3.1Aspirin should be offered to all patients after an MI, and should be continued indefinitely (Grade A).
6.1.3.2Clopidogrel should not be offered as first-line monotherapy after an MI (Grade A).
6.1.3.3Clopidogrel, in combination with low-dose aspirin, is recommended for use in the management of non-ST-segment-elevation acute coronary syndrome in people who are at moderate to high risk of MI or death (Grade A).1
6.1.3.4People at moderate to high risk of MI or death, presenting with non-ST- segment-elevation acute coronary syndrome can be determined by clinical signs and symptoms, accompanied by one or both of the following:
  • the results of clinical investigations, such as new ECG changes (other than persistent ST segment elevation) indicating ongoing myocardial ischaemia, particularly dynamic or unstable patterns
  • the presence of raised blood levels of markers of cardiac cell damage such as troponin (Grade A).1
6.1.3.5Treatment with clopidogrel in combination with low-dose aspirin should be continued for 12 months after the most recent acute episode of non-ST- segment-elevation acute coronary syndrome. Thereafter, standard care, including treatment with low-dose aspirin alone, is recommended unless there are other indications to continue dual antiplatelet therapy (Grade A).1
6.1.3.6After an ST-segment-elevation MI, patients treated with a combination of aspirin and clopidogrel during the first 24 hours after the MI should continue this treatment for at least 4 weeks. Thereafter, standard treatment including low-dose aspirin should be given, unless there are other indications to continue dual antiplatelet therapy (Grade A).
6.1.3.7If the patient has not been treated with a combination of aspirin and clopidogrel during the acute phase of an MI, this combination should not routinely be initiated (GPP).
6.1.3.8The combination of aspirin and clopidogrel is not recommended for routine use for any longer than 12 months after the acute phase of MI, unless there are other indications to continue dual anti-platelet therapy, and the combination is usually recommended for a shorter duration after an ST-elevation MI (Grade A).
6.1.3.9For patients with aspirin hypersensitivity, clopidogrel monotherapy should be considered as an alternative treatment (Grade B).
6.1.3.10In patients with a history of dyspepsia, treatment with a proton pump inhibitor and low-dose aspirin should be considered in line with‘Dyspepsia. NICE clinical guideline 17’ (Grade A).
6.1.3.11After appropriate treatment, patients with a history of aspirin-induced ulcer bleeding whose ulcers have healed and who are negative for Helicobacter pylori should be considered for treatment with a full-dose proton pump inhibitor and low-dose aspirin. Refer to ‘Dyspepsia. NICE clinical guideline17’ (Grade A).

6.1.4. Beta blockers recommendations

Hyperlink to the related evidence statements

6.1.4.1Early after an acute MI, all patients without left ventricular systolic dysfunction or with left ventricular systolic dysfunction (symptomatic or asymptomatic) should be offered treatment with a beta-blocker (Grade A).
6.1.4.2For patients after an MI with left ventricular systolic dysfunction, who are being offered treatment with a beta-blocker, clinicians may prefer to consider treatment with a beta-blocker licensed for use in heart failure (Grade B).
6.1.4.3Beta-blockers should be continued indefinitely after an acute MI (GPP).
6.1.4.4After a proven MI in the past, all patients with left ventricular systolic dysfunction should be offered treatment with a beta-blocker whether or not they have symptoms, and those with heart failure plus left ventricular systolic dysfunction should be managed in line with ‘Chronic heart failure. NICE clinical guideline 5’ (Grade A).
6.1.4.5After a proven MI in the past, patients with preserved left ventricular function who are asymptomatic should not be routinely offered treatment with a beta-blocker, unless they are identified to be at increased risk of further CVD events, or there are other compelling indications for beta- blocker treatment (GPP).
6.1.4.6Beta-blockers should be initiated as soon as possible when the patient is clinically stable and titrated upwards to the maximum tolerated dose (GPP).

6.1.5. Vitamin K antagonists recommendations

Hyperlink to the related evidence statements

6.1.5.1For patients who have had an MI, high-intensity warfarin (INR >3) should not be considered as an alternative to aspirin in first-line treatment (Grade A).
6.1.5.2For patients who have had an MI and are unable to tolerate either aspirin or clopidogrel, treatment with moderate-intensity warfarin (INR 2–3) should be considered for up to 4 years, and possibly longer (Grade A).
6.1.5.3For patients who have had an acute MI, are intolerant to clopidogrel and have a low risk of bleeding, treatment with aspirin and moderate-intensity warfarin (INR 2–3) combined should be considered (GPP).
6.1.5.4For patients already being treated for another indication (mechanical valve, recurrent deep vein thrombosis, atrial fibrillation, left ventricular thrombus), warfarin should be continued. For patients treated with moderate-intensity warfarin (INR 2–3) and who are at low risk of bleeding, the addition of aspirin should be considered (Grade B).
6.1.5.5The combination of warfarin and clopidogrel is not routinely recommended (GPP).

6.1.6. Calcium channel blockers recommendations

Hyperlink to related evidence statements

6.1.6.1Calcium channel blockers should not routinely be used to reduce cardiovascular risk after an MI (Grade A).
6.1.6.2If beta-blockers are contraindicated or need to be discontinued, diltiazem or verapamil may be considered for secondary prevention in patients without pulmonary congestion or left ventricular systolic dysfunction. (Grade B).
6.1.6.3For patients who are stable after an MI, calcium channel blockers may be used to treat hypertension and/or angina. For patients with heart failure, amlodipine should be used, and verapamil, diltiazem and short-acting dihydropyridine agents should be avoided in line with ‘Chronic heart failure. NICE clinical guideline 5’ (Grade A).

6.1.7. Potassium channel activators recommendations

Hyperlink to the related evidence statements

6.1.7.1Nicorandil is not recommended to reduce cardiovascular risk in patients after an MI (Grade A).

6.1.8. Aldosterone antagonists in patients with heart failure and LV dysfunction recommendations

Hyperlink to related evidence statements

6.1.8.1For patients who have had an acute MI and who have symptoms and/orsigns of heart failure and left ventricular systolic dysfunction, treatment with an aldosterone antagonist licensed for post-MI treatment should be initiated within 3–14 days of the MI, preferably after ACE inhibitor therapy (Grade B).
6.1.8.2Patients who have recently had an acute MI and have clinical heart failure and left ventricular systolic dysfunction, but who are already being treated with an aldosterone antagonist for a concomitant condition (for example, chronic heart failure), should continue with the aldosterone antagonist or an alternative, licensed for early post-MI treatment (GPP).
6.1.8.3For patients who have had a proven MI in the past and heart failure due to left ventricular systolic dysfunction, treatment with an aldosterone antagonist should be in line with ‘Chronic heart failure. NICE clinical guideline 5’ (GPP).
6.1.8.4Renal function and serum potassium should be monitored before and during treatment with an aldosterone antagonist. If hyperkalaemia is a problem, the dose of the aldosterone antagonist should be halved or the drug stopped (GPP).

6.1.9. Statins and other lipid lowering agents recommendations

Hyperlink to related evidence statements

6.1.9.1Statin therapy is recommended for adults with clinical evidence of cardiovascular disease in line with ‘Statins for the prevention of cardiovascular events’ (NICE technology appraisal guidance 94).3
6.1.9.2After an MI, all patients should be offered treatment with a statin as soon as possible (GPP).
6.1.9.3The decision whether to initiate statin therapy should be made after an informed discussion between the healthcare professional and the individual about the risks and benefits of statin treatment, and taking into account additional factors such as comorbidities and life expectancy (GPP).
6.1.9.4Baseline liver enzymes should be measured before initiation of a statin (GPP).
6.1.9.5Patients who have raised liver enzymes should not routinely be excluded from statin therapy (GPP).
6.1.9.6When the decision has been made to prescribe a statin, it is recommended that therapy should usually be initiated with a drug with a low acquisition cost (taking into account required daily dose and product price per dose) (Grade A).
6.1.9.7Patients who are intolerant of statins should be considered for other lipid lowering agents (GPP).
6.1.9.8Routine monitoring of creatine kinase in asymptomatic patients who are being treated with a statin after an MI is not recommended (Grade A).
6.1.9.9Patients who are being treated with a statin and who develop muscle symptoms (pain, tenderness or weakness) should be advised to seek medical advice so that creatine kinase can be measured (Grade A).
6.1.9.10The dose of any statin may need to be reduced or stopped if there are issues surrounding the metabolic pathway, food and/or drug interactions and/or concomitant illness (GPP).
6.1.9.11Statins should be discontinued in patients who develop peripheral neuropathy that may be attributable to the statin treatment, and further advice from a specialist should be sought (Grade A).

Introduction

Pharmacotherapy is an important part of the treatment which should be offered for secondary prevention after MI. This chapter reviews the evidence for each of the different agents, and makes specific recommendations on which drugs should be offered. The recommendations generally refer to drug classes, and fall within licensed indications. However, other drugs have been included if there is evidence of clinical effectiveness. Where appropriate drugs should be prescribed in doses and at a frequency shown to be effective in the clinical trials. If this is not possible, this should be to the maximum tolerated.

The majority of drugs are intended as long term therapy, and it is clearly stated if any drugs should be routinely discontinued after an interval. However, some patients may wish to review the benefits of long term treatment. This requires a careful assessment and discussion of individual tolerance and preference, balanced against the magnitude of benefit in risk reduction. The risk reducing benefit is influenced by the level of individual patient risk and in some cases referral for specialist advice may be appropriate.

It is the responsibility of the individual prescriber to review each patient for the following, referring to the British National Formulary (www.bnf.org.uk) as appropriate;

  • indications
  • drug
  • doses
  • contra-indications
  • supervision and monitoring
  • product characteristics

6.2. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs)

6.2.1. Evidence statements for ACE inhibitors and ARBs

6.2.1.1Short term treatment with an ACE inhibitor in unselected patients immediately after an MI was associated with a small reduction in mortality (1++).
6.2.1.2Long term treatment with an ACE inhibitor in patients with signs of heart failure and or left ventricular systolic dysfunction who have recently experienced an MI was associated with substantial reduction in all-cause mortality, recurrent MI and readmission for heart failure (1++).
6.2.1.3In patients with chronic heart failure and left ventricular systolic dysfunction, including patients who had had an MI in the past, treatment with ACE inhibitors improved life expectancy and reduced the risk of hospitalisation for heart failure (1++).
6.2.1.4In stable patients with coronary artery disease without heart failure or known left ventricular systolic dysfunction, long term treatment with an ACE inhibitor was associated with a modest reduction in total and cardiovascular mortality, non-fatal MI and coronary revascularisation (1++).
6.2.1.5Long term treatment with an ACE inhibitor in patients after MI with heart failure or left ventricular systolic dysfunction, with or without heart failure is cost effective when compared to placebo.
6.2.1.6In stable patients with coronary artery disease without heart failure or known left ventricular systolic dysfunction, long term treatment with an ACE inhibitor was cost effective.
6.2.1.7No trials were found which looked at the effectiveness of an ARB compared with placebo in patients after acute MI.
6.2.1.8In one small trial of patients with stable coronary artery disease, without heart failure or left ventricular systolic dysfunction, treatment with an ARB compared to placebo was associated with a reduction in the composite end point of revascularisation, non-fatal MI and cardiovascular death (1−).
6.2.1.9In one study, although not in a second, there were fewer cardiovascular deaths in patients treated with an ACE inhibitor compared to in those treated with an ARB (1++)
6.2.1.10There were no trials found comparing treatment with an ACE inhibitor and an ARB which included patients early after MI without heart failure or left ventricular systolic dysfunction.
6.2.1.11There was no difference in total mortality or cardiovascular mortality and morbidity in patients with heart failure and or left ventricular systolic dysfunction treated within 10 days of acute MI with the combination of an ACE inhibitor and ARB compared to those treated with either agent alone (1++).
6.2.1.12In patients with chronic heart failure and left ventricular systolic dysfunction, including patients who had had an MI in the past, treatment with an ARB did not improve life expectancy compared to treatment with an ACE inhibitor (1++).
6.2.1.13A post hoc analysis showed a reduction in investigator reported hospitalisation for MI or heart failure in patients with heart failure and or LV systolic dysfunction treated within 10 days of acute MI with the combination of an ACE inhibitor and ARB compared to those treated with either agent alone (1++).
6.2.1.14No trials were found comparing frequent with less frequent monitoring of renal function.
6.2.1.15Patients after MI with renal dysfunction are at higher risk of adverse cardiovascular outcomes than those with normal renal function (2+).
6.2.1.16No randomised controlled trials were found of treatment with ACE inhibitors and or ARBs in patients after acute MI with a serum creatinine > 220mmol/l or in the majority, a serum potassium of 5.6 mmol/l or more.
6.2.1.17In patients after MI with a serum creatinine of up to 220 mmol/l, ACE Inhibitor treatment was associated with a significant reduction in cardiovascular events regardless of the baseline renal function (2+).
6.2.1.18Treatment with an ACE inhibitor and ARB combined in patients after MI was associated with an increased risk of renal dysfunction (1++).

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6.2.2. Clinical effectiveness of ACE inhibitors

6.2.2.1. Unselected patients

A meta analysis of 18 randomised controlled trials in unselected patients immediately following an acute MI found that ACE inhibitor treatment improved survival compared with placebo (OR 7%, 95% CI 2% to 11% by a fixed effects model, OR 7%, 95% CI −1% to 14% by a random effects model), (National Institute for Clinical Excellence 2001). Trial follow up ranged from 3 days to 19 months. However, the majority of patients were randomised in two large trials (ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group. 1995) (Gruppo Italiano per lo Studio della Sopravvivenza nell’infarto Miocardico. 1994) in which recruitment was within the first 24 hours of MI and the follow up duration was five and six weeks respectively.

6.2.2.2. Patients with left ventricular systolic dysfunction

A meta analysis of six randomised controlled trials of patients who had experienced an acute MI and who had heart failure and or left ventricular systolic dysfunction found that ACE inhibitor treatment increased survival compared with placebo (OR 26%, 95% CI 17% to 34% by a fixed effects model, OR 26%, 95% CI 14% to 38% by a random effects model) (National Institute for Clinical Excellence 2001). The duration of follow up in the trials ranged from 2 weeks to 42 months, and all but one had at least six months follow up.

In a study of patients with anterior MI and systolic blood pressure ≥ 100 mmHg early (day 1) initiation of the ACE inhibitor ramipril compared with delayed initiation (day 14) was associated with attenuation of left ventricular remodelling and a more rapid recovery of left ventricular ejection (Pfeffer, M. A. et al 1997).

6.2.3. Clinical Effectiveness of long term ACE inhibitor therapy

Patients with preserved left ventricular function

A meta analysis of six randomised controlled trials in patients with stable coronary artery disease (CAD) and preserved left ventricular function found that treatment with an ACE inhibitor compared to placebo was associated with a reduction in cardiovascular mortality (RR 0.83, 95% CI 0.72 to 0.96), non-fatal MI (RR 0.84, 95% CI 0.75 to 0.94), all-cause mortality (RR 0.87, 95% CI 0.81 to 0.94), and coronary revascularisation rates (RR 0.93, 95% CI 0.85 to 1.00) (Al-Mallah, M. H. et al 2006). Mean duration of follow up was 4.4 years, range 2 to 4.8 years. The majority of patients were recruited to three large trials (Arnold, J. M. O. et al 2003) (Braunwald, E. et al 2004) (Fox, K. M. and EUROPA investigators 2003) in which 53%, 65% and 55% respectively had had a prior MI, at least one month earlier in one trial (Arnold, J. M. O., Yusuf, S., Young, J. et al 2003) and at least three months in the other two trials (Braunwald, E. et al 2004) (Fox, K. M. and EUROPA investigators 2003).

Patients with left ventricular systolic dysfunction

A systematic review of long term trials of patients after MI with left ventricular systolic dysfunction identified 3 large trials which each recruited more than 1000 patients with a minimum follow up of one year. Assignment to treatment with an ACE inhibitor, initiated between 3 and 16 days after an acute MI, was associated with a reduction in mortality (OR 0.74, 95% CI 0.66 to 0.83), readmission for heart failure (OR 0.73, 95% CI 0.63 to 0.85) and recurrent MI (OR 0.80, 95% CI 0.69 to 0.94) compared with placebo, over a median follow up of 31 months (Flather, M. D. et al 2000). With the inclusion in the meta analysis of two randomised control trials of patients with reduced left ventricular systolic function, with (SOLVD Investigators 1991) or without (SOLVD Investigators 1992) symptoms of heart failure, the findings were similar. Seventy five percent of patients in these other two trials had a previous history of MI.

A 12 year follow up study of the SOLVD trials, in which 75% of participants had a previous MI (SOLVD Investigators 1991) (SOLVD Investigators 1992) found a reduction in all-cause mortality (OR 0.90, 95% CI 0.84 to 0.95) and cardiac deaths in those assigned for the duration of the trial to ACE inhibitor treatment compared to those assigned to placebo (Jong, P. et al 2003). This result was consistent in both the prevention trial which recruited asymptomatic patients, and the treatment trial which recruited patients with symptomatic CHF. A follow up study of a randomised controlled trial which recruited patients with left ventricular systolic dysfunction 3 to 7 days after acute MI (Pfeffer, M. A., Braunwald, E., Moye, L. A. et al 1992) found that at 12 years, patients who had been assigned to ACE inhibitor treatment during the original trial period for 2 to 4 years had a reduced risk of all-cause mortality (RR 0.89, 95% CI 0.80 to 0.99), all-cause hospitalisation (RR 0.92, 95% CI 0.88 to 0.96), and cardiovascular hospitalisations (RR 0.95, 95% CI 0.91 to 1.00) (Buch, P. et al 2005). Randomised controlled trials of the effectiveness of ACE inhibitor treatment in patients with chronic heart failure and left ventricular systolic dysfunction, which included patients with an MI in the past, is examined in The NICE guideline Chronic Heart Failure: national clinical guideline for diagnosis and management in primary and secondary care, 2003 (National Collaborating Centre for Chronic Conditions. 2003). These guidelines state that systematic reviews of randomised controlled trials comparing ACE inhibitor to placebo have found that ACE inhibitor therapy in patients with heart failure due to left ventricular systolic dysfunction increases life expectancy compared to placebo. The effect is more marked in patients with more severe LV systolic impairment, or more severe symptoms, although there is benefit for all New York Heart Association functional classes (NYHA). Compared with placebo, ACE inhibitor therapy also reduces the risk of hospitalisation for heart failure in such patients, and also for patients with asymptomatic left ventricular systolic dysfunction.

6.2.4. Clinical effectiveness of ARBs

Only one trial comparing an ARB with placebo in patients after MI without chronic heart failure was found. This was a small un-blinded study which randomised 406 patients with CAD, of which 69% had a previous MI, to treatment with candesartan or placebo. Treatment with candesartan was associated with a reduction in the primary endpoint which was the combination of revascularisation, non-fatal MI and cardiovascular mortaliy (P < 0.03) (Kondo, J. et al 2003). There were no studies found which specifically examined the efficacy of treatment with an ARB in asymptomatic patients with left ventricular dysfunction.

6.2.5. Clinical Effectiveness of ACE inhibitors versus ARBs

No randomised controlled trials were identified that evaluated treatment with an ARB compared to treatment with an ACE inhibitor in patients with acute MI and preserved left ventricular function.

Two randomised controlled trials compared treatment with an ACE inhibitor to an ARB in patients with acute MI complicated by left ventricular systolic dysfunction and found no significant difference in all-cause mortality between the two groups (Dickstein, K., Kjekshus, J., and OPTIMAAL Steering Committee of the OPTIMAAL Study Group 2002) (Pfeffer, M. A. et al 2003). One randomised controlled trial showed a non significant difference in all-cause mortality (RR 1.13, 95% CI 0.99 to 1.28) and a significant reduction in cardiovascular mortality in favour of the ACE inhibitor captopril compared with the ARB losartan (RR 1.17, 95% CI 1.01 to 1.34) (Dickstein, K., Kjekshus, J., and OPTIMAAL Steering Committee of the OPTIMAAL Study Group 2002), although in the second study there was no significant difference in mortality between treatment with the ACE inhibitor captopril and the ARB valsartan (HR 1.00, 95% CI 0.90 to 1.11) (Pfeffer, M. A., McMurray, J. J., Velazquez, E. J. et al 2003). Treatment with the ARB losartan was better tolerated than with the ACE inhibitor captopril in one trial (Dickstein, K., Kjekshus, J., and OPTIMAAL Steering Committee of the OPTIMAAL Study Group 2002).

Randomised controlled trials of the effectiveness of ARB treatment in patients with chronic heart failure and left ventricular systolic dysfunction, including those with an MI in the past, were reviewed in the NICE guideline Chronic Heart Failure: national clinical guideline for diagnosis and management in primary and secondary care, 2003 (National Collaborating Centre for Chronic Conditions. 2003). This guideline recognised that the evidence for ARB treatment in patients with chronic heart failure was still emerging and at the time of publication none of the ARBs were licensed for use in heart failure in the UK. Several large randomised trials were ongoing, but at the time that the NICE guideline for chronic heart failure were published, ARBs had not been shown to increase life expectancy compared to ACE inhibitor therapy for patients with heart failure due to left ventricular systolic dysfunction in several randomised controlled trials. However, the 2003 NICE guideline for the management of chronic heart failure states; ‘ARBs may provide an alternative to ACE inhibitors for patients intolerant of ACE inhibitors (for example, because of cough)’

Adverse effects of ACE inhibitors were reported for three trials included in the systematic review of treatment with an ACE inhibitor in patients with left ventricular systolic dysfunction (Flather, M. D., Yusuf, S., Kober, L. et al 2000). Hypotension and renal dysfunction occurred more frequently in the ACE inhibitor treated group.

A randomised controlled trial conducted in patients with symptomatic heart failure and left ventricular systolic dysfunction, who were not receiving ACE inhibitors due to previous intolerance, found that patients were more likely to stop treatment with the ARB candesartan than placebo due to renal dysfunction (6.1% versus 2.7% in all patients, respectively), hyperkalaemia (1.9% versus 0.3% in all patients, respectively) and hypotension (3.7% versus 0.9% in all patients, respectively) (Granger, C. B. et al 2003). Patients were more likely to stop treatment with candesartan for a particular reason if they had previously been intolerant to treatment with an ACE inhibitor for the same reason.

Based on the available evidence the guideline development group came to the decision that treatment with an ARB should be considered as a second line alternative to an ACE inhibitor for those individuals with a documented history of ACE inhibitor intolerance.

6.2.6. Clinical effectiveness of ACE inhibitors plus ARBs versus ARBs or ACE inhibitors

A randomised controlled trial of patients within 0.5 to 10 days of an acute MI complicated by left ventricular systolic dysfunction compared treatment with the combination of an ARB plus an ACE inhibitor with an ACE inhibitor alone, or an ARB alone. During a median follow up of 24.7 months, treatment with the combination of the ARB valsartan and the ACE inhibitor captopril had no effect on all-cause mortality (HR 0.98, 95% CI 0.90 to 1.09), cardiovascular mortality (RR 1.00, 95% CI 0.89 to 1.11), non-fatal MI or hospitalisation for heart failure compared either with captopril alone or valsartan alone (Pfeffer, M. A., McMurray, J. J., Velazquez, E. J. et al 2003). Combination therapy was associated with an increased rate of adverse events compared with either captopril alone or valsartan alone.

Randomised controlled trials of the effectiveness of ACE inhibitor and ARB treatment combined in patients with chronic heart failure and left ventricular systolic dysfunction, which included patients with an MI in the past, is examined in The NICE guideline Chronic Heart Failure: national clinical guideline for diagnosis and management in primary and secondary care, 2003 (National Collaborating Centre for Chronic Conditions. 2003). This guideline states that one systematic review of 17 randomised controlled trials demonstrated that the combination of ARBs and ACE inhibitors did not reduce risk of mortality as compared to ACE inhibitors on their own. However, significantly fewer patients required hospitalisation with the dual therapy. A large randomised controlled trial reported similar effects on mortality and hospitalisation with worsening heart failure. It was recognized that at the time of publication other trials were in progress which would further inform the use of the combination of ACE inhibitors and ARBs in patients with chronic heart failure (National Collaborating Centre for Chronic Conditions. 2003).

6.2.7. Clinical effectiveness of renal function and ACE inhibitor / ARB treatment

No studies were identified of post MI patients with poor renal function that specifically addressed at what level of renal function the risks of therapy with ACE inhibitors outweigh the benefits. Post hoc analysis of a randomised controlled trial of patients with, or at high risk of, CAD with mild renal insufficiency found that the cumulative incidence of the primary outcome (cardiovascular death, non-fatal MI or stroke) was higher in patients with renal insufficiency compared to those without, and also increased with serum creatinine concentration. ACE inhibitor treatment with ramipril reduced the subsequent risk of cardiovascular events in patients with and without renal insufficiency, without increasing adverse events (Mann, J. F. E. et al 2001). A second post hoc analysis of a randomised controlled trial in post MI patients with left ventricular dysfunction showed that treatment with the ACE inhibitor captopril reduced cardiovascular events irrespective of baseline kidney function (Tokmakova, M. P. et al 2004).

The 2003 NICE Guideline: Chronic heart failure: Management of chronic heart failure in adults in primary and secondary care stated that it is very rarely necessary to stop an ACE inhibitor and that clinical deterioration is likely if treatment is withdrawn (National Collaborating Centre for Chronic Conditions. 2003).

6.2.8. Health economics of ACE inhibitors in patients after MI with LV systolic dysfunction, or with heart failure

Ten studies were found which compared the use of ACE inhibitors in selected patients after MI with left ventricular systolic dysfunction with and without heart failure, or with heart failure. Nine studies used effectiveness data from studies of patients early after MI; five from the AIRE study, (Schadlich, P. K., Huppertz, E., and Brecht, J. G. 1998) (Martinez, C. and Ball, S. G. 1995) (Anderson, A. N., Moodley, I., and Kropman, K. 2000) (Erhardt, L. et al 1997) (Hart, W. M. et al 2002) three from the SAVE study (Mantovani, L. G., Belisari, A., and Szucs, T. D. 1998) (Michel, B. C. et al 1996) (Tsevat, J. et al 1995) and one from the TRACE study (LePen, C. et al 1998). The tenth study (Cook, J. R. et al 1998) used effectiveness data from the SOLVD trial in which 66% patients in the treatment study and 80% in the prevention study had a previous history of MI.

The NICE guidelines for the diagnosis and management of chronic heart failure in primary and secondary care also makes recommendation for treatment with ACE inhibitors in patients with heart failure due to left ventricular systolic dysfunction, including patients with chronic heart failure and a history of an MI in the past. This guideline states that ‘Treatment of heart failure with ACE inhibitors is cost effective, largely due to the costs saved from the reduced risk of hospitalisation. Treatment can be cost saving and has very favorable cost effectiveness ratios even when conservative assumptions are employed.’

The AIRE Study (Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. 1993) recruited patients with clinical heart failure early after acute MI, and examined the effectiveness of treatment with ramipril compared with placebo. Five studies examined cost effectiveness based on the AIRE study (Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. 1993) in different healthcare systems.

A Spanish study (Hart, W. M., Rubio-Terres, C., Pajuelo, F. et al 2002) found that compared with placebo, the incremental cost per life year gained with ramipril ranged between Euro 4784 in year 1 to Euro 1550 in the fourth year. The sensitivity analyses showed that the estimated cost per LYG was robust to wide variations in the baseline values.

A South African study (Anderson, A. N., Moodley, I., and Kropman, K. 2000) assessed the cost effectiveness of ramipril compared to placebo. The results were stratified according to age. The use of ramipril results in an incremental cost/life year gained, which ranges between R67 907 (approximately £6200) in the first year to R16 808/LYG (approximately £1500) in the fourth year. When the quality of life of the patients was taken into account, the cost-utility analysis shows an incremental cost/QALY of R21 382 (approximately £1900) for those younger than 65 years of age and R18 029 (approximately £1600) for those older than 65 years of age. The results were robust in sensitivity analyses.

A German study (Schadlich, P. K., Huppertz, E., and Brecht, J. G. 1998) reported an estimated ICER for ramipril compared to placebo of DM 2456/life year gained after 3.8 years (approximately £1100) and DM 8271/LYG (approximately £3650) for the first year. Monte-Carlo simulation results showed that ramipril was cost effective, dominating the alternative in 5% of the cases. In 99% of the cases the ICER ranged between DM 2500 to DM 8500 suggesting that ramipril is highly cost effective.

A Swedish study (Erhardt, L., Ball, S., Andersson, F. et al 1997) reported incremental cost effectiveness ratios of treatment with ramipril compared with placebo over 3 treatment periods: 1, 2, and 3.8 years. The ICERs ranged from SEK 33 033 for the 1-year treatment to (approximately £2800) SEK 14 148 (approximately £1200) for the 3.8-year treatment period. Two way-sensitivity analyses indicated that the study results were robust although hospital costs had an impact on the ICERs.

Finally, a UK based study (Martinez, C. and Ball, S. G. 1995), reported cost/life years gained from treatment with ramipril compared to placebo ranging between £425 for the first year to £286 in the fourth year. These results were not sensitive to the timeframe of the model, but were sensitive to changes in hospitalisation costs.

The SAVE study recruited patients early after acute MI without symptoms of heart failure and a left ventricular ejection fraction of equal to, or less than, 40%, and examined the effectiveness of treatment with captopril compared to placebo. Three studies examined cost effectiveness in different healthcare systems.

An Italian study (Mantovani, L. G., Belisari, A., and Szucs, T. D. 1998) reported an incremental cost per death avoided with captopril treatment of 33, 229 million lira (approximately £13 800). The cost/life year gained was 14, 708 million lira (approximately £6100). The model was sensitive to changes in values of the prices of captopril, cost of revascularisation procedures, the number of cardiovascular deaths prevented, and the number of years of life saved.

A Dutch study (Michel, B. C., Al, M. J., Remme, W. J. et al 1996) estimated the costs and effects of treatment. The cost per life year gained with captopril treatments was DF122 887 (approximately £2350) at 4 years. Costs per life-year gained for 20 years of treatment was estimated at DF115 729 (approximately £1600), with 95% of all estimates between DF10 and DF150 000 for the 20 year treatment. The results were sensitive to the cost of captopril and the occurrence and prevention of clinical heart failure, although the authors did not report by how much the result would change.

An American study (Tsevat, J., Duke, D., Goldman, L. et al 1995) developed a Markov model from a US third payer’s perspective to assess the cost effectiveness of captopril compared to placebo. The model used two scenarios based on assumptions about death rates with captopril versus placebo beyond 4 years. The first scenario included equal mortality rates, whilst the second extrapolated a difference in mortality for the remaining time in the model. In the first scenario, the ICER of captopril ranged from $3600/QALY (approximately £2000) for 80-year old patients to $60 800/QALY (approximately £34 500) for 50-year old patients. In the second scenario, ICERs ranged from $3700 to $10 400/QALY, depending on age. The model was robust to changes in estimates of variables when they were varied individually over wide ranges for patients aged over 60 years, but for those aged 50 years it was only sensitive to the cost of captopril and changes in utilities.

The TRACE study (Kober, L. et al 1995) recruited patients early after acute MI with left ventricular systolic dysfunction (corresponding to a left ventricular ejection fraction ≤ 35%) and examined the effectiveness of treatment with trandolapril compared with placebo.

A French study (LePen, C., Lilliu, H., Keller, T. et al 1998) evaluated the cost effectiveness of trandolapril. The cost/life year saved was 6950 French francs (approximately £900). Probabilistic sensitivity analyses showed that in 7.4% of the cases trandolapril use was cost saving (trandolapril dominated placebo) and in 92.6% of the cases the ICER was positive, and still within the acceptable ranges of cost/LYS, lying between FF 8410 (95%CI 7990 to 8840) according to the bootstrap method (approximately £1050).

The SOLVD trials recruited patients with left ventricular systolic dysfunction (ejection fraction ≤ 35%) with (SOLVD Investigators 1991) and without (SOLVD Investigators 1992) symptoms of heart failure and examined the effectiveness of treatment with enalapril compared to placebo. At baseline, 66% and 80% of patients respectively had a history of MI. One study was found examining cost effectiveness of ACE inhibitors using SOLVD data from the prevention arm.

One study (Cook, J. R., Glick, H. A., Gerth, W. et al 1998) based on US costs modelled the long-term economic and clinical impact of using enalapril versus usual therapy for hypertensive patients with left ventricular dysfunction. Enalapril dominated the alternative (more effective and less costly) in the base-case. These results were robust in sensitivity analysis. The cost effectiveness acceptability curve showed that there was a less than 10% probability that enalapril treatment would increase the costs in comparison with placebo, and less than 3% probability that the cost per life-year gained would exceed $3,000 (approximately £1800) in the trial observation period analysis. In the lifetime projection analysis, the probability that enalapril dominated placebo was 94%.

In summary treatment with ACE inhibitors compared to placebo is cost effective in patients early after MI with left ventricular systolic dysfunction, with and without heart failure. Treatment with ACE inhibitors in patients with heart failure and left ventricular systolic dysfunction, which includes those with an MI in the past, has previously been reported as cost effective in the NICE guideline for the diagnosis and management of chronic heart failure in primary and secondary care.

6.2.9. Health economics of ACE inhibitors in patients after MI with preserved LV function

Five studies were found which addressed this question, (Malik, I. S., Bhatia, V. K., and Kooner, J. S. 2001) (Aurbach, A. et al 2004) (Smith, M. G., Neville, A. M., and Middleton, J. C. 2003) (Backhouse, M. E., Richter, A., and Gaffney, L. 2000) (Bjorholt, I. et al 2002). The use of ACE inhibitors was compared with placebo in MI patients without left ventricular systolic dysfunction but at high risk of cardiovascular events. All five studies used data from the HOPE study which examined the effectiveness of treatment with ramipril compared to placebo, and in which 53% had a history of a previous MI at least 1 month earlier. Two were UK studies (Backhouse, M. E., Richter, A., and Gaffney, L. 2000) (Malik, I. S., Bhatia, V. K., and Kooner, J. S. 2001).

The first UK study (Backhouse, M. E., Richter, A., and Gaffney, L. 2000) constructed a decision analytical model to estimate long-term benefits and costs of treatment with ramipril compared to placebo from the NHS perspective. The base-case analysis showed a discounted ICER of £5544 per LYG. The ICERs did not vary substantially with age. For example the ICER reduces to £2814 for those aged 52 year while increasing to £10 291 in for those aged 80 years due to differences in life expectancy.

The second UK study (Malik, I. S., Bhatia, V. K., and Kooner, J. S. 2001) assessed treatment with ramipril compared to placebo in patients with different risks of cardiovascular death classified as low, medium and high. The cost effectiveness of ramipril for the base case analysis was £14 700 (5 years) and £2800 (lifetime treatment). These results were sensitive to drug costs as well as pre-treatment risk. The costs of ACE inhibitors have fallen since this study was done.

Three studies have examined the cost effectiveness of treatment with ramipril compared to placebo in three other healthcare systems.

The first study (Smith, M. G., Neville, A. M., and Middleton, J. C. 2003) assessed the clinical and economic impacts of treatment with ramipril in an Australian high-risk population. The incremental cost effectiveness analysis showed the estimated cost per life-year saved to be A$17 214, 95% CI (A$8 338 to 39 536), approximately (£6600/LYG) The results were sensitive to risk of cardiovascular death, cost and risk of revascularisation.

The second study (Aurbach, A., Russ, W., Battegay, E. et al 2004) modelled the cost effectiveness of ramipril in patients with an increased risk of cardiovascular events, including a subgroup of patients with diabetes, in a Swiss context. The incremental cost effectiveness ratio of ramipril versus placebo was CHF 6 005 per life-year gained in the base case analysis (approximately £2500/LYG). The diabetic population had a much more favourable ICER of CHF 3790/LYG (approximately £1600).The results remained robust in sensitivity analysis and showed that ramipril was cost effective in more than 90% of the cases, if society was willing to pay up to CHF10000/LYG (approximately £4100) per additional LYG.

The third study (Bjorholt, I., Andersson, F. L., Kahan, T. et al 2002) evaluated the long-term treatment with ramipril in patients at high risk of cardiovascular events in a Swedish context. The estimated ICERs were SEK 16 600/LYG (approximately £1200) when direct medical costs for cardiovascular reasons only were considered and SEK 45 400/LYG (approximately £3400) when direct medical costs for all diseases were considered. Using quality of life weights from the literature they found that the cost/QALY to be SEK 26 600 (approximately £2000). The results were sensitive to reduction in life expectancy at the end of the trial period.

An additional analysis was undertaken to examine the cost effectiveness of treatment with ACE inhibitors compared to placebo in patients with preserved left ventricular dysfunction. The analysis used effectiveness data from a meta analysis (Al-Mallah, M. H., Tleyjeh, I M., Abdel-Latif, A. A. et al 2006) which meta analysed data from six trials (Braunwald, E., Domanski, M. J., Fowler, S. E. et al 2004) (Nissen, S. E. et al 2004) (Fox, K. M. and EUROPA Investigators 2003) (Arnold, J. M. O., Yusuf, S., Young, J. et al 2003) (MacMahon, S. et al 2000) (Pitt, B. et al 2001). A Markov model was developed to evaluate the incremental costs and effects of lifetime treatment with ACE inhibitors from a UK NHS perspective. The results suggested treatment with ACE inhibitors was cost effective with an estimated ICER of about £3400/QALY gained for men and about £3700 for women compared with placebo; well below the level considered affordable in the NHS (about £20 000 to £30 000 per QALY). This was robust in sensitivity analysis.

In conclusion treatment with ACE inhibitors in patients with an MI at least 1 month earlier and preserved left ventricular function is cost effective. See Appendix C for the full model.

6.3. Antiplatelet therapy

6.3.1. Evidence statements for antiplatelet therapy

6.3.1.1After an MI, treatment with aspirin reduces the risk of death and cardiovascular events (1++).
6.3.1.2In a subgroup of patients with recent MI, aspirin and clopidogrel have similar cardiovascular benefits (1++).
6.3.1.3Long term treatment with aspirin is more cost effective compared to clopidogrel in the management of occlusive vascular events.
Patients after non-ST segment elevation MI
6.3.1.4Clopidogrel plus aspirin therapy was significantly more effective than placebo plus aspirin in patients with non-ST elevation acute coronary syndrome for the combination endpoint of death from cardiovascular causes, non-fatal MI or stroke (1++). Refer to the NICE Technology Appraisal Clopidogrel in Non-ST segment elevation acute coronary syndromes.
6.3.1.5In patients with a non ST segment elevation acute coronary syndrome, treatment with aspirin plus clopidogrel compared to aspirin alone for 12 months is cost effective.
Patients after ST segment elevation MI
6.3.1.6In one study of patients scheduled for fibrinolytic therapy, presenting within 12 hours of a ST elevation MI or with new left bundle branch block, treatment with clopidogrel in addition to other standard therapy, for a median of 4 doses reduced the composite end point of an occluded infarct-related artery or reinfarction or death if these occurred before angiography was performed. At 30 days in this same study, there was a reduction in the composite end point of cardiovascular death, recurrent MI or recurrent ischaemia leading to the need for urgent revascularisation. In a second study of patients presenting within 24 hours of a suspected acute MI, (87% STEMI), treatment with clopidogrel for a mean duration of 14.9 days in addition to standard therapy, reduced the risk of the composite endpoint of death, reinfarction or stroke. There was no significant increased risk of major bleeding (1+).
6.3.1.7In a study of a mean duration of 28 months that recruited patients with either clinically evident cardiovascular disease or multiple vascular risk factors, the treatment with clopidogrel in addition to other standard therapy was not associated with a reduction in the combination outcome of first occurrence of cardiovascular death, MI, or stroke, compared with standard therapy (1++).
Aspirin
6.3.1.8Aspirin intolerance is defined as either
  • a proven hypersensitivity to aspirin, or
  • a history of severe indigestion caused by low-dose aspirin
Definition taken from NICE IFP on the TA for ‘Clopidogrel and modified-release dipyridamole in the prevention of occlusive vascular events’.
6.3.1.9In patients who have had aspirin-induced ulcer bleeding that has been appropriately treated and are H pylori negative, treatment with aspirin plus high dose proton pump inhibitor has been shown to have a lower risk of recurrent bleeding episodes than treatment with clopidogrel alone (1++).

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6.3.2. Clinical effectiveness of antiplatelet agents

A meta analysis of randomised control trials of antiplatelet therapy in high risk patients (Baigent, C. et al 2002) identified 12 trials on patients with a history of MI. A total of 20 006 patients were allocated to a mean duration of 27 months of therapy.

For patients after MI, treatment resulted in 36 (standard error 5) fewer serious vascular events per 1000 (non-fatal MI: 18 (SE 3) fewer per 1000, P < 0.001; vascular death: 14 (SE 4) fewer per 1000 P < 0.0006; non-fatal stroke: 5 (SE 1) fewer per 1000, P < 0.002). The estimated risk of extra-cranial bleeding due to antiplatelet therapy was calculated as approximately 1 patient per 1000 per year. Six of the 12 trials compared aspirin with placebo, three used a combination of aspirin and dipyridamole, and one used sulphinpyrazone. Five of the six aspirin trials were available for review (Elwood, P. C. et al 1974) (Elwood, P. C. and Sweetnam, P. M. 1979) (Aspirin Myocardial Infarction Study Research Group. 1980), (Coronary Drug Project Research Group. 1980) (Breddin, K. et al 1979). Of these, one randomised controlled trial found a reduction in non-fatal MI (7.1% versus 10.9%, P < 0.05) (Elwood, P. C. and Sweetnam, P. M. 1979) and another a reduction in mortality (5.8% versus 8.3%, Z value - 1.9) (Coronary Drug Project Research Group. 1980).

Two short-term randomised control trials that recruited post MI patients within 24 hours of infarction found that aspirin therapy reduced mortality (RR 0.78, 95% CI 0.71 to 0.85) (Baigent, C. et al 1998) and reinfarction (P < 0.03) (Verheugt, F. W. et al 1990).

6.3.2.1. Antiplatelet therapy in patients who are aspirin intolerant

Literature searching did not identify any studies of patients after MI with aspirin sensitivity

Post-hoc analysis of the CURE trial (Yusuf, S. et al 2001) found that bleeding risk increased with aspirin dose, with or without clopidogrel, without any increase in efficacy (HR 1.9, 95% CI 1.29 to 2.72 in the placebo group, HR 1.6, 95% CI 1.19 to 2.23 in the clopidogrel group, HR 1.7, 95% CI 1.36 to 2.20 in the combined group) (Peters, R. J. et al 2003).

A randomised control trial has been conducted on patients at high vascular risk (CAD, cerebrovascular insufficiency and/or peripheral vascular disease) and also with ulcer bleeding which could have been gastric or duodenal. The patients were all Helicobacter pylori negative before randomisation. The study found that treatment with aspirin plus esomeprazole was superior to clopidogrel plus placebo in the prevention of recurrent bleeding (0.7%, 95% CI 0% to 2%, versus 8.6%, 95% CI 4.1 to 13.1%, P = 0.001). No patients were treated with the combination of clopidogrel and esomeprazole (Chan, F. K. et al 2005).

6.3.2.2. Clinical effectiveness of aspirin versus clopidogrel

In patients after recent MI, treatment with aspirin was as effective as clopidogrel in reducing the combined risk of ischaemic stroke, MI, or vascular death in a randomised control trial which recruited stroke, peripheral artery disease and post MI patients.(Gent, M. 1996).

6.3.2.3. Clinical effectiveness of aspirin versus aspirin plus clopidogrel

Patients after non-ST segment elevation MI

A Health Technology Appraisal examined clopidogrel use in combination with aspirin compared with aspirin alone in the treatment of non-ST segment elevation acute coronary syndromes (National Institute for Clinical Excellence. 2004). One randomised control trial was identified (Yusuf, S., Zhao, F., Mehta, S. R. et al 2001). Clopidogrel in addition to aspirin was significantly more effective than placebo plus aspirin in patients with non-ST elevation acute coronary syndromes for the composite outcome of death from cardiovascular causes, non-fatal MI or stroke over the mean 9 month treatment period (RR 0.80, 95% CI 0.72 to 0.90). There were significantly more patients with major bleeds in the clopidogrel group (RR 1.38, 95% CI 1.13 to 1.67), but there were not significantly more patients with episodes of life-threatening bleeding or haemorrhagic strokes (RR 1.21, 95% CI 0.95 to 1.56).

Patients after ST elevation MI

A randomised control trial of patients presenting within 12 hours of a ST segment elevation MI or with new left bundle branch block examined the effectiveness of the addition of clopidogrel to aspirin, fibrinolytic therapy, and, where appropriate, heparin (Sabatine, M. S. et al 2005). Participants received a median of 4 doses of study medication and were scheduled to undergo coronary angiography 48 to 192 hours after the start of treatment. Clopidogrel reduced the composite primary end point of occluded infarct-related artery, or reinfaction or death if these occurred before angiography was performed (OR 20%, P < 0.03).The study was not powered to detect a survival benefit, and had a short clinical follow up of 30 days. At 30 days, treatment with clopidogrel was associated with a reduction in the composite end point of cardiovascular death, recurrent MI or recurrent ischaemia leading to the need for urgent revascularisation. The rates of major bleeding and intracranial haemorrhage were similar in the two groups.

A randomised control trial which recruited patients within 24 hours of a suspected acute MI found that the addition of clopidogrel to aspirin and other standard treatment reduced the risk of the primary endpoint of the combination of death, reinfarction or stroke, compared with aspirin treatment alone (OR 0.91, 95% CI 0.86 to 0.97) (Chen, Z. M. et al 2005a). Clopigogrel plus aspirin also reduced the risk of the co-primary endpoint of all-cause mortality (OR 0.93, 95% CI 0.87 to 0.99). Follow up was until hospital discharge or for up to 4 weeks, and mean duration of trial treatment in survivors was 14.9 days, 87% of patients had ST elevation MI and 6% left bundle branch block. The rate of fatal and non-fatal bleeding was low and similar in both treatment groups.

A randomised control trial recruited patients with either clinically evident cardiovascular disease or multiple vascular risk factors (Bhatt, D. L. et al 2006). Patients received clopidogrel plus aspirin or placebo plus aspirin. Thirty five percent of patients had had a prior MI in the previous 5 years. Forty eight percent of patients had documented coronary artery disease in the previous five years. The median follow up time of the study was 28 months. For the primary endpoint (combination of first occurrence of cardiovascular death, MI, or stroke) there was no benefit observed in patients who received clopidogrel plus aspirin compared with those who received placebo plus aspirin. For the principal secondary endpoint (combination of MI, stroke, death from cardiovascular causes, hospitalisation for unstable angina, transient ischaemic attack, or revascularisation), clopidogrel plus aspirin treatment did reduce the event rate compared to aspirin therapy alone. For the other secondary endpoints (death from all-causes, cardiovascular death, non-fatal MI, non-fatal ischaemic stroke, and non-fatal stroke) there was no difference observed between the two treatment groups (Bhatt, D. L., Fox, K. A. A, Hacke, W. et al 2006).

In pre-specified subgroup analysis of participants with ‘symptomatic’ (previous cardiovascular disease) and ‘asymptomatic’ patients with no multiple risk factors were designated ‘asymptomatic’ (of whom some did have a history of reported cardiovascular events) it was found that asymptomatic patients treated with clopidogrel plus aspirin had an increase in the rate of primary events, in all-cause mortality and cardiovascular mortality compared with those treated with aspirin alone. In contrast, the symptomatic patients treated with clopidogrel plus aspirin had a marginally significant reduction in the rate of primary events compared with patients treated with aspirin therapy alone (6.9% versus 7.9% respectively, P = 0.046), although there was no significant effect on death from cardiovascular causes (Bhatt, D. L., Fox, K. A. A, Hacke, W. et al 2006).

Clopidogrel plus aspirin treatment was associated with an increase in moderate bleeding (bleeding which led to transfusion, but did not fulfil the criteria for severe bleeding) compared with the placebo plus aspirin treatment (RR 1.62, 95% CI 1.27 to 2.1). Severe bleeding, fatal bleeding and primary intracranial haemorrhage events were similar in the two comparison groups (Bhatt, D. L., Fox, K. A. A, Hacke, W. et al 2006).

In summary, only two trials were identifird that examined the effectiveness of clopidogrel plus aspirin treatment versus aspirin alone in patients immediately after ST elevation MI (Sabatine, M. S., Cannon, C. P., Gibson, C. M. et al 2005) (Chen, Z. M., Jiang, L. X., Chen, Y. P. et al 2005a). The combination treatment was not studied beyond 4 weeks and hence it is not clear if there is any further benefit of contininuing combination treatment in the longer term for patients after an ST elevation MI.

6.3.3. Health economics of clopidogrel versus aspirin in the management of occlusive vascular events

Aspirin is widely available and cheap, whilst clopidogrel is more expensive. A review was undertaken to establish if the additional costs of clopidogrel are worth the extra gains in quality adjusted survival in patients after an acute MI. Four studies were found that met the inclusion criteria examining the cost effectiveness of aspirin compared to clopidogrel (Jones, L. et al 2004) (Schleinitz, M. D., Weiss, J. P., and Owens, D. K. 2004) (Karnon, J. et al 2005) (Annemans, L. et al 2003). One of these studies (Jones, L., Griffin, S., Palmer, S. et al 2004) was a Health Technology Assessment (HTA). In this section, only the results of the HTA are summarised. And the other papers’s evidence tables are in the appendix.

The HTA (Jones, L., Griffin, S., Palmer, S. et al 2004) assessed the clinical and cost effectiveness of clopidogrel in the secondary prevention of occlusive vascular events (OVE) in patients with vascular disease The incremental cost effectiveness ratio (ICERs) for the lifetime model excluding the effect of treatment on vascular death is £31 400/QALY. The short term model had an ICER of about £17 000/QALY. The probability that clopidogrel is cost effective was 48% for the life time treatment and 71% for the short term model at £30 000/QALY threshold. These results are sensitive to the inclusion/exclusion of the relative risk of vascular death in the model. In the lifetime model the ICERs rise to £94 448/QALY and short term model they rise to £21 448/QALY when the effect of treatment on vascular death is included.

In conclusion, the use of clopidogrel compared with aspirin is unlikely to be cost effective especially in the long term at £30 000/QALY threshold. In the short term, clopidogrel has been found to be cost effective in the wider population of patients with occlusive vascular disease, but it is unclear if this is applicable to the whole population of patients after acute MI.

6.3.4. Health economics of clopidogrel plus aspirin versus aspirin in patients with non-ST segment elevation MI

Seven studies were found which met the inclusion criteria (Main, C. et al 2004) (Fiore, L. D. et al 2002) (Latour-Perez, J. et al 2004) (Schleinitz, M. D. and Heidenreich, P. A. 2005) (Gaspoz, J.-M. et al 2002) (Lindgren, P. et al 2005). (J. Karnon , A. Bakhai b A. Brennan A. Pandor M. Flather E. Warren D. Gray R. Akehurst 2006) In this section, only the results of the HTA are summarised, and the other papers’s evidence tables are in the appendix.

The HTA (Main, C., Palmer, S., Griffin, S. et al 2004) was undertaken in the UK and assessed the cost effectiveness of clopidogrel plus aspirin compared to placebo plus aspirin in patients with non-ST segment elevation acute coronary syndrome. The results from the base-case model suggested that treatment with clopidogrel as an adjunct to aspirin for 12 months compared to aspirin alone was cost effective as long as the health service was willing to pay £6078/QALY. These results were robust in sensitivity analysis. When the time horizon was reduced from 40 years to 5 years the ICERs increased to £14 844/QALY with a 71% probability that clopidogrel compared to placebo will be cost effective if the NHS was willing to pay £30 000/QALY. The authors explored the cost effectiveness of using clopidogrel for periods shorter than 1 year. The strategies of using clopidogrel for 3 or 6 months were ruled out by extended dominance, and the ICER for 12 months of treatment with clopidogrel compared with 1 month was £5159 per QALY, with a 83% probability that clopidogrel is cost effective at £30 000/QALY. These results remained robust even in low risk populations.

In conclusion, clopidogrel used as an adjunct to aspirin is cost effective in patients with non-ST segment elevation acute coronary syndrome; including those with non ST segment elevation MI, although the evidence derives largely from a single trial. Duration of clopidogrel treatment affects the cost effectiveness, with more favourable ICERs obtained in the first three months. Current evidence suggests that clopidogrel can not be recommended beyond 12 months.

6.4. Beta blockers

6.4.1. Evidence statements for beta blockers

6.4.1.1In unselected patients after acute MI, long-term treatment, (greater than 6 months and up to 4 years) with beta blockers resulted in 1.2% annual risk reduction and 23% reduced odds of death compared with placebo (1++).
6.4.1.2In one randomised controlled trial of patients after acute MI with LV systolic dysfunction, treatment with carvedilol, in addition to ACE inhibitor therapy, reduced all-cause mortality, cardiovascular-cause mortality, non-fatal MI, and the combination of all-cause mortality or non-fatal MI (1++).
6.4.1.3Carvedilol compared to placebo is cost effective in patients with LV dysfunction.
6.4.1.4In patients after acute MI with asymptomatic left ventricular systolic dysfunction, beta blocker treatment reduced cardiovascular mortality and the risk of developing CHF (2+).
6.4.1.5There is inconclusive evidence about the optimum time to initiate beta - blocker treatment in patients after an MI.
6.4.1.6There is no evidence that unselected patients after acute MI treated with a beta blocker should routinely stop treatment.
6.4.1.7No trials were found which examined the effectiveness of initiating beta blocker treatment in patients with a proven MI in the past and preserved left ventricular function.
6.4.1.8In randomised controlled trials, initiation of beta blocker treatment in patients with chronic heart failure, of whom some had had a previous MI, reduced mortality and the need for hospitalisation. (NICE Chronic Heart Failure guideline) (1++).

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6.4.2. Clinical effectiveness of beta blockers

6.4.2.1. In unselected patients

A meta analysis of 51 short term randomised controlled trials (up to 6 weeks) of treatment with beta blockers in patients after acute MI, found a non significant reduction in the odds of death compared with placebo (Freemantle, N. et al 1999). In a more recent short term randomised controlled trial in patients recruited within 24 hours of a suspected acute MI and with a mean follow up of 16 days after MI, intravenous beta blocker treatment followed by oral therapy did not reduce total mortality in hospital (Chen, Z. M. et al 2005b). Beta blocker therapy reduced the risk of reinfarction (OR 0.82, 95% CI 0.72 to 0.89) and ventricular fibrillation (OR 0.83, 95% CI 0.75 to 0.93), although there was an increase in the risk of cardiogenic shock (OR 1.30, 95% CI 1.19 to 1.41). The excess of cardiogenic shock was mainly during days 0 to 1, whereas the reduction in risk of ventricular fibrillation and reinfarction emerged more gradually.

An observational study of post MI patients aged 65 years or older found that the rate of in-hospital mortality was lower in patients treated with beta blockers compared with untreated patients (mortality rate: 5.1% and 8.1% respectively, P≤0.001), even after adjustment for baseline differences in demographic, clinical, and treatment characteristics between the two groups (OR 0.81, 95% CI 0.75 to 0.87) (Krumholz, H. M. et al 1998).

A meta analysis of 31 long term randomised controlled trials (6 weeks to 48 months) found that treatment with beta blockers in patients after acute MI reduced the odds of death by 23% compared with placeb (pooled random effects, OR 0.77, 95% CI 0.69 to 0.85) (Freemantle, N., Cleland, J., Young, P. et al 1999). The number needed to treat for one year to avoid one death was 84. Individually, four out of nine beta blockers were found to significantly reduce the odds of death, namely propranolol (OR 0.71, 95% CI 0.59 to 0.85), timolol (OR 0.59, 95% CI 0.46 to 0.77), metoprolol (OR 0.80, 95% CI 0.66 to 0.96), and acebutolol (OR 0.49, 95% CI 0.25 to 0.93). The randomised controlled trials that included propranolol, timolol and metoprol made up 63% of the available evidence in the meta analysis. The evidence for acebutolol was supported by a single moderately sized study which is open to considerable measurement error.

No randomised controlled trials were found comparing different times for initiating beta blocker therapy after acute MI. However, a separate analysis of the meta analysis of long term randomised controlled trials showed that an initial intravenous dose of beta blocker had no additional benefit on mortality, although there was no reason to delay treatment (Freemantle, N., Cleland, J., Young, P. et al 1999).

No randomised trials were found which compared the effectiveness of different available beta blockers. However, the Cooperative Cardiovascular Project (Gottlieb, S. S., McCarter, R. J., and Vogel, R. A. 1998) examined the two year survival of patients after MI, and reported outcomes in patients prescribed different beta blockers. This survey was based on the entire population of acute care hospital claims for acute MI to the Health Care Financing Administration for Medicare for an 8 month period, with data staggered so that most discharges fell between February 1994 and July 1995. 69 338 patients after MI were prescribed a beta blocker on discharge (metoprolol 65%, atenolol 25%, propranolol 6%, other 4%). Overall, patients treated with any beta blocker on discharge had a 40% reduction in mortality compared with those not treated with a beta blocker. Those prescribed metoprolol and atenolol had very similar survival rates after 1 and 2 years of follow up, while patients discharged on propranolol had a lower survival rate (Gottlieb, S. S. and McCarter, R. J. 2001).

Literature searching did not identify any randomised controlled trials of initiating beta blocker treatment in unselected patients with a proven MI in the past (greater than 1 years).

No randomised controlled trials were identified which examined the effectiveness of continued beta blocker treatment in patients treated after an acute MI. A follow up study after a 3 year randomised trial examined the effect of the withdrawal of the beta blocker metoprolol during a mean of 51 months. After beta blocker withdrawal the number of deaths, reinfarctions or cerebrovascular events in patients previously assigned to a beta blocker was not significantly different to the number of events in patients assigned to placebo (Olsson, G. et al 1988). However, patients who had had a further MI within the last year before withdrawal were not included, and a third of patients who stopped beta blocker treatment restarted treatment, for clinical indications. A further follow up study was conducted after a 3 year randomised controlled trial comparing beta blocker therapy with timolol versus placebo in patients after acute MI. In patients who survived the entire period, beta blocker prescription increased gradually to 28.7% in the previously allocated placebo group, and decreased to 59.5% in the previously allocated beta blocker group, whereas in those who died beta blocker therapy was prescribed less frequently 18.6% and 44.3%, respectively (Pedersen, T. R. 1985). During follow up, the mortality curves of the two groups identified by the original randomisation to timolol treatment or placebo continued to rise in parallel, demonstrating a consistent effect on mortality over the period of the observation period. The mortality curves for patients divided by age (less than 65 years, or 65 years and older) showed the same pattern.

A systematic review examined the incidence of fatigue, sexual dysfunction and depression in randomised placebo controlled trials of beta blocker therapy. Fatigue occurred more frequently, and was more likely to lead to withdrawal from treatment in patients assigned to beta blockers compared to in those assigned to placebo. The occurrence of sexual dysfunction was similar in the two groups, although more patients in the beta blocker group withdrew from treatment due to sexual dysfunction. There was no difference in the incidence of depressive symptoms (Ko, D. T. et al 2002).

6.4.2.2. Patients with left ventricular systolic dysfunction and or heart failure

A meta regression analysis assessed the extent to which inclusion of patients with heart failure or evidence of major cardiac dysfunction influenced the outcome of randomised controlled trials of beta blocker therapy in patients with a history of MI. Treatment may have begun at any stage after MI, and may have commenced intravenously (Houghton, T., Freemantle, N., and Cleland, J. G. 2000). There was a non significant interaction between treatment with beta blockers and the presence of heart failure, and the authors concluded that there is a lack of evidence to show that the relative benefits of beta blockers after MI are different in patients with or without heart failure, but that the absolute benefit may be greater in the former because of a higher baseline risk of heart failure and death.

A more recent randomised placebo controlled trial examined the effectiveness of beta blocker treatment with carvedilol in addition to other standard current therapy in patients after acute MI with reduced left ventricular function (ejection fraction ≤ 40%). Patients were recruited within 3 to 21 days of an acute MI, 46% had had thrombolysis or primary angioplasty and 97% were treated with an ACE inhibitor. Trial follow up was for a mean of 1.3 years and a minimum of 3 months, and all-cause mortality (HR 0.77, 95% CI 0.60 to 0.98), cardiovascular mortality (HR 0.75, 95% CI 0.58 to 0.96), non-fatal MI (HR 0.59, 95% CI 0.39 to 0.90), and the combination of all-cause mortality or non-fatal MI (HR 0.71, 95% CI 0.57 to 0.89) was lower in those treated with carvediolol compared with placebo (Dargie, H. J. 2001).

Randomised controlled trials of the effectiveness of beta blocker treatment in patients with chronic heart failure and left ventricular systolic dysfunction, which included patients with an MI in the past is examined in The NICE guideline Chronic Heart Failure: national clinical guideline for diagnosis and management in primary and secondary care, 2003 (National Collaborating Centre for Chronic Conditions. 2003). This guideline states that many large clinical trials reviewed in four meta-analyses, and one subsequent randomised controlled trial, have shown that several beta blockers increase life expectancy in patients with heart failure due to LV systolic dysfunction compared with placebo. The best evidence exists for bisoprolol, carvediol and modified-release metoprolol, while there is little evidence for other beta blockers. There are no randomised controlled trials of atenolol, or some other commonly used beta blockers, in patients with heart failure.

6.4.2.3. Patients with asymptomatic left ventricular dysfunction

No randomised controlled trials were identified that assessed beta blocker therapy only in patients with asymptomatic LV dysfunction.

A post hoc analysis of a randomised controlled trial examining the effectiveness of ACE inhibitor therapy versus placebo in early post MI patients with left ventricular dysfunction without overt heart failure (Pfeffer, M. A., Braunwald, E., Moye, L. A. et al 1992) found that beta blocker usage was associated with a reduction in the risk of cardiovascular death and the development of CHF (Vantrimpont, P. et al 1997).

Two studies examined the impact of beta blocker treatment in patients with a previous MI. A post hoc analysis of a randomised controlled trial of ACE inhibitor therapy versus placebo in asymptomatic patients with left ventricular dysfunction, in which 75% had a history of MI (SOLVD Investigators 1992), found that beta blocker usage was associated with a lower mortality rate compared with placebo (P = 0.01) (Exner, D. V. et al 1999).

An observational study in elderly patients with prior MI and asymptomatic left ventricular systolic dysfunction examined four patient treatment groups: treatment with beta blockers alone, treatment with ACE inhibitors alone, treatment with the combination of beta blockers and ACE inhibitors, and no treatment. Follow up ranged from a mean of 19 to 34 months. Compared with no treatment, there was a reduction in new coronary events of 25% by treatment with beta blockers alone (P = 0.001), of 17% by treatment with ACE inhibitors alone (P = 0.001), and of 37% by treatment with the combination of beta blockers and ACE inhibitors (P = 0.001). Compared with no treatment, the development of CHF was reduced by 41% with beta blocker treatment alone (P = 0.001), by 32% with ACE inhibitors alone (P = 0.001), and by 60% with the combination of beta blockers and ACE inhibitors (P = 0.001) (Aronow, W. S., Ahn, C., and Kronzon, I. 2001).

6.4.3. Health economics of beta blockers

Two studies from outside the UK comparing beta blockers and placebo were appraised. A Swedish study (Olsson, G., Levin, L.-A., and Rehnqvist, N. 1987) was a cost consequence study which compared metoprolol with placebo enumerating arrays of health outcome measures alongside costs. Effectiveness data were drawn from the Stockholm Metoprolol study which included 66% post MI patients. The use of beta blockers resulted in a reduction of cardiovascular events and the cost per patient for metoprolol treated participants was Kr 118610 (approximately £11 981) compared to Kr 137220 (approximately £13 861) for participants in the control arm. However there was no difference in mortality.

An American cost effectiveness analysis (Goldman, L. et al 1988) used effectiveness data from a pooled meta analysis of beta blocker trials conducted by the authors. Results were stratified by age and risk groups. Risk was defined as low, medium and high risk of mortality observed in a 15 year prognostic study The age groups were 45, 55 or 65 years. The authors explored two possibilities in their analysis. One was a conservative assumption that observed treatment gains will cease immediately once the treatment is stopped, and another that the gains will gradually disappear. The cost/LYG ranged between $23 457 for a low risk 45 year old man to $3609/LYG for a high risk 65 year old man using a conservative assumption. When a best guess assumption is used the cost/LYG ranged between $12 855 for a low risk 45 year old man to $2427/LYG for a high risk 65 year old man.

Mortality risk was the major cost effectiveness driver and age did not affect the cost effectiveness ratios (ICERs), The ICERs for the low risk groups were over 5 fold the ICERs for the high risk groups for all age groups.

An additional analysis was undertaken to inform the decisions of the guideline group. This examined the cost effectiveness of treatment with the beta blocker, carvedilol, in patients with left ventricular systolic dysfunction who met the inclusion criteria of the CAPRICORN trial (Dargie, H. J. 2001). A Markov model was developed to evaluate the incremental costs and effects of lifetime treatment from a UK NHS perspective, and the base case results were presented for 65-year-old men and women early after MI with left ventricular dysfunction. The results suggested that treatment with carvedilol is highly cost effective for this population with an ICER of about £1100/QALY gained, compared with placebo which is well below the level usually considered to be affordable in the NHS (about £20 000 to £30 000 per QALY).

In conclusion treatment with beta blockers compared to placebo in patients early after MI is cost effective. This conclusion for unselected patients is based on two non-UK studies. However, given the substantial clinical effectiveness of beta blockers and their cost, it is highly unlikely that any new cost effectiveness study will conclude differently. The findings in patients with left ventricular systolic dysfunction are robust and the use of beta blockers in these patients is cost effective.

6.5. Vitamin K antagonists

6.5.1. Evidence statements for vitamin K antagonists

6.5.1.1In patients after acute MI high-intensity warfarin compared to placebo is associated with reduction in cardiovascular events and mortality (Grade 1+).
6.5.1.2There is inconsistent evidence that high-intensity warfarin is more effective than aspirin in reduction of mortality or reinfarction and stroke (Grade 1+).
6.5.1.3High-intensity warfarin is associated with a higher incidence of major bleeding compared to aspirin (1+).
6.5.1.4Treatment with aspirin is likely to be more cost effective when compared with with warfarin in patients with CAD.
6.5.1.5In patients after acute MI, the combination of low intensity warfarin and aspirin did not consistently reduce the incidence of major cardiovascular events compared to aspirin on its own, and was associated with an increased risk of haemorrhagic complications (1+).
6.5.1.6In patients after an acute MI, the combination of moderate intensity warfarin (target INR 2 to 2.5) and aspirin compared to aspirin on its own resulted in a reduction in the composite end point of death, non- fatal MI or stroke (1+).
6.5.1.7In patients after an acute MI, the combination of moderate intensity warfarin (target INR 2 to 2.5) and aspirin compared to aspirin on its own was associated with an increased risk of bleeding (Grade 1+).
6.5.1.8In patients after acute MI, the combination of moderate intensitywarfarin (target INR 2 to 2.5) and aspirin did not reduce the incidence of major cardiovascular events compared to high intensity warfarin (target INR 2.8 to 4.2) on its own, and was associated with a similar risk of bleeding (Grade 1+).

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6.5.2. Clinical effectiveness of vitamin K antagonists

6.5.2.1. Introduction

Oral anticoagulants have been used in patients with vascular disease for over 40 years, but their role is controversial due to a number of reasons. Firstly, initial randomised control trials in patients who have experienced an MI have provided conflicting results. Secondly, anticoagulants are inconvenient to use because they require careful monitoring and dose adjustment, and in clinical trials may be more closely managed than in everyday clinical practice. Thirdly, there is debate over whether the associated risk of bleeding justifies their use. Fourthly, antiplatelet therapies have proven to be effective in reducing vascular complications and to be relatively safe.

Two important findings directed further research on anticoagulants in CAD. Rates of recurrent vascular events in patients with suspected unstable angina or MI without initial ST elevation remained high, despite the use of antiplatelet agents (Yusuf, S. et al 1998). In addition, there was evidence of persistent biochemical stimulus to thrombosis for several months after an acute MI and in unstable angina patients, even in the presence of aspirin (Merlini, P. A. et al 1994).

These observations stimulated a number of large well conducted randomised controlled trials examining anticoagulation therapy at different intensities with and without concomitant aspirin therapy. Initially randomised controlled trials tested high intensity anticoagulation therapy, International normalised ratio (INR) = 2.8 to 4.8, versus placebo (Smith, P. 1992), (Van Bergen, P. F. M. M. et al 1994). The INR is a value derived from a standardized laboratory test that measures the effect of anticoagulant. The laboratory materials used in the test are calibrated against internationally accepted reference preparations, so that variability between laboratories and different reagents is minimized. Normal blood has an INR of 1. Therapeutic anticoagulation often aims to achieve an INR value of 2.0 to 3.5. More recent randomised controlled trials have evaluated anticoagulants versus aspirin (Hurlen, M. et al 2002) (van Es, R. F. et al 2002) and the combination of anticoagulants and aspirin versus aspirin alone (Hurlen, M., Abdelnoor, M., Smith, P. et al 2002) (van Es, R. F., Jonker, J. J., Verheugt, F. W. et al 2002) (Coumadin Aspirin Reinfarction Study (CARS) Investigators. 1997) (Fiore, L. D., Ezekowitz, M. D., Brophy, M. T. et al 2002) (Herlitz, J. et al 2004) with anti-coagulation treatment in the moderate-intensity (INR = 2 to 3), and the low intensity (INR < 1.5) ranges.

6.5.2.2. Vitamin K antagonists

Two randomised control trials compared high intensity anticoagulant therapy with placebo in patients early after acute MI, both with mean follow up times of 37 months (Smith, P. 1992) (Van Bergen, P. F. M. M., Jonker, J. J. C., Van der Meer, F. J. M. et al 1994). One study found that warfarin treatment resulted in a significant reduction in all-cause mortality (RR 24%, 95% CI 4% to 44%), reinfarction (RR 34%, 95% CI 19% to 54%) and stroke (RR 55%, 95% CI 30% to 30 to 77%) (Smith, P. 1992). The second study showed that nicoumalone or phenprocoumon treatment led to no reduction in all-cause mortality; however anticoagulant therapy did reduce recurrent MI (HR 0.47, 95% CI 0.38 to 0.59), vascular (HR 0.65, 95% CI 0.55 to 0.76) and cerebrovascular events (HR 0.60, 95% CI 0.40 to 0.90) (Van Bergen, P. F. M. M., Jonker, J. J. C., Van der Meer, F. J. M. et al 1994). In both studies, treatment was associated with significantly more major bleeding episodes compared with placebo (Smith, P. 1992) (Van Bergen, P. F. M. M., Jonker, J. J. C., Van der Meer, F. J. M. et al 1994).

A meta analysis of 16 randomised controlled trials of oral anticoagulant therapy in patients with established CAD found that high intensity anticoagulant therapy (INR > 2.8) reduced total mortality (OR 22%, 95% CI 13% to 31%), reinfarction (OR 42%, 95% CI 34% to 48%) and stroke (OR 48%, 95% CI 33% to 60%) compared with control, although it was associated with increased major bleeding (Anand, S. S. and Yusuf, S. 1999). Meta analysis of 4 randomised controlled trials of moderate intensity anticoagulation therapy (INR 2 to 3) found that anticoagulation treatment only reduced reinfarction compared with control (OR 52%, 95% CI 37% to 64%), and was also associated with increased major bleeding (Anand, S. S. and Yusuf, S. 1999).

6.5.2.3. Vitamin K antagonists compared to aspirin alone

Meta analysis of 7 randomised control trials in patients with CAD found that, compared with aspirin, moderate- or high-intensity anticoagulant therapy did not reduce the risk of all-cause mortality, reinfarction or stroke (Anand, S. S. and Yusuf, S. 1999). Major bleeding was increased with anticoagulant therapy. Subsequent to the publication of this meta analysis, two randomised controlled trials showed that high-intensity anticoagulant therapy was more effective than aspirin treatment for reducing the combination endpoint of death, non-fatal MI or stroke (warfarin versus aspirin, RR 0.81, 95% CI 0.69 to 0.95) (Hurlen, M., Abdelnoor, M., Smith, P. et al 2002) (coumadin versus aspirin, HR 0.55, 95% CI 0.3 to 1.00) (van Es, R. F., Jonker, J. J., Verheugt, F. W. et al 2002). In the first study which recruited patients with acute MI, anticoagulation therapy compared to aspirin treatment reduced the risk of reinfarction (warfarin versus aspirin: RR 0.74, 95% CI 0.55 to 0.98) and thromboembolic stroke (warfarin versus aspirin: RR 0.52, 95% CI 0.28 to 0.97) but not mortality during a trial follow up of approximately four years (Hurlen, M., Abdelnoor, M., Smith, P. et al 2002). In contrast, the second study found anticoagulation treatment did reduce risk of mortality compared to aspirin treatment (coumadin versus aspirin: HR 0.28, 95% CI 0.09 to 0.82), with no difference for reinfarction and stroke (van Es, R. F., Jonker, J. J., Verheugt, F. W. et al 2002). This study recruited patients with acute coronary syndrome of which 88% had an MI and the mean follow up was 26 months.

6.5.2.4. Vitamin K antagonists plus aspirin compared to aspirin alone

A randomised controlled trial in patients within 42 days of an acute MI and a mean follow up of 5 years found that low-dose warfarin added to aspirin therapy did not reduce the risk of the combination of cardiovascular death, reinfarction, although it did reduce the risk of stroke (aspirin 7.1% versus aspirin + warfarin 4.7%, P = 0.004) when compared to aspirin therapy alone. The combination increased the risk of bleeding (Herlitz, J., Holm, J., Peterson, M. et al 2004). Two further randomised controlled trials in patients with an acute MI up to 3 weeks earlier did not demonstrate any clinical benefit of the combination of aspirin and low intensity anticoagulation therapy over aspirin monotherapy (Coumadin Aspirin Reinfarction Study (CARS) Investigators. 1997) (Fiore, L. D., Ezekowitz, M. D., Brophy, M. T. et al 2002), although there was a significant increase in major bleeding associated with the combination. Low intensity warfarin therapy was used for these studies: one study achieved an INR of 1.04 with 1 mg warfarin plus aspirin treatment and 1.19 with 3 mg warfarin plus aspirin treatment (Coumadin Aspirin Reinfarction Study (CARS) Investigators. 1997) The second study achieved a mean INR value of 1.8 (Fiore, L. D., Ezekowitz, M. D., Brophy, M. T. et al 2002).

Two randomised controlled trials compared moderate intensity anticoagulant therapy (INR 2.0 to 2.5) plus aspirin with aspirin alone (Hurlen, M., Abdelnoor, M., Smith, P. et al 2002) (van Es, R. F., Jonker, J. J., Verheugt, F. W. et al 2002). One study in patients with acute coronary syndrome of which 88% had an MI found that moderate intensity coumadin therapy was more effective than aspirin alone in reducing coronary events and all-cause mortality (HR 0.28, 95%CI 0.09 to 0.82). A mean INR of 2.4 was achieved and the mean follow up was 26 months. Major bleeding rates were low in both groups. Minor bleeding in the aspirin plus coumadin group was significantly higher compared with the aspirin alone group (van Es, R. F., Jonker, J. J., Verheugt, F. W. et al 2002). The second study in patients hospitalised for acute MI found that aspirin plus warfarin therapy led to a lower risk of the combination outcome of death, non-fatal infarction or thromboembolic stroke compared with aspirin alone (RR 0.71, 95% CI 0.60 to 0.83) (Hurlen, M., Abdelnoor, M., Smith, P. et al 2002). Warfarin plus aspirin therapy was associated with an increased risk of non-fatal bleeding compared to aspirin alone (Hurlen, M., Abdelnoor, M., Smith, P. et al 2002). Trial follow up was for approximately four years and a mean INR of 2.2 was achieved.

6.5.2.5. Vitamin K antagonists plus aspirin compared to warfarin alone

A randomised control trial that compared moderate intensity warfarin treatment plus aspirin with high intensity warfarin treatment alone found the combination treatment did not reduce the risk of the combination endpoint of death, non-fatal reinfarction or thromboembolic stroke compared to warfarin monotherapy. The bleeding risk was similar in the two groups (Hurlen, M., Abdelnoor, M., Smith, P. et al 2002).

6.5.3. Health economics of vitamin K antagonists

6.5.3.1. Warfarin compared to placebo

One non UK study was identified which examined the cost effectiveness of warfarin compared with placebo (Van Bergen, P. F. M. M. et al 1995). This was a cost minimisation analysis and was undertaken in Holland. The authors used effectiveness data from the Anticoagulation in the Secondary Prevention of Events in Coronary Thrombosis (ASPECT) study and AntiPlatelets Trialists Collaboration study (APT). The total cost was Dfl 17 671 813 (approximately £6800 000) for the warfarin group and Dfl 19 222 590 (approximately £7400 000) for the placebo group. The savings per patient due to the intervention, discounted at 5%, was Dfl 906 (approximately £350). The incremental cost of intervention was negative suggesting that anticoagulation administration results in savings compared to placebo. These results were robust in sensitivity analysis.

6.5.3.2. Warfarin compared to aspirin

One Italian study was identified which compared warfarin with aspirin (Gianetti, J., Gensini, G., and De, Caterina R. 1998).

Gianetti et al assessed the cost effectiveness of warfarin compared to aspirin, for secondary prevention of CAD, within a European context. The authors used effectiveness data from the ASPECT and the APT. This was a cost minimisation analysis since they did not synthesize the costs and benefits.

Costing was done using three different methods, which all yielded comparable results. The total cost per patient per year, using DRG mean total costs, was ECU2, 150 (approximately £1660) for warfarin and ECU2187 (approximately £1680) for aspirin. Results were sensitive to variations in the aspirin-warfarin efficacy ratio. This is a ratio that lies between 0 and 1. If the ratio is 1 or close to 1, it means there is no difference in efficacy between two interventions while the further away from 1 it follows there is a big difference in effectiveness between interventions. Warfarin was no longer the cost effective strategy in Italy once an efficacy ratio of approximately 0.72 is reached. From this analysis, it would appear that the cost effectiveness of warfarin relative to aspirin would be relatively favourable. However if the results of WARIS II are considered which found the efficacy ratio of 0.81, it appears that aspirin is the cost effective strategy compared to warfarin.

In conclusion the cost effectiveness of warfarin relative to aspirin is unclear, but largely weighs in favour of aspirin especially in light of the new evidence which shows that the efficacy ratio can be as high as 0.81.

6.6. Calcium channel blockers

6.6.1. Evidence statements for calcium channel blockers

6.6.1.1In a meta analysis of trials with unselected patients after MI diltiazem or verapamil treatment was associated with a reduction in non-fatal infarction, but there was no effect on all-cause mortality (1++).
6.6.1.2In a randomised controlled trial of unselected patients after MI, verapamil treatment for a mean of 16 months was associated with a reduction in the combined major events of death or first reinfarction and the combined major cardiac events of cardiac death and first reinfaction. Sub-group analysis showed that this benefit was confined to patients without heart failure (1+).
6.6.1.3In a randomised controlled trial of patients after MI, diltiazem treatment during a mean follow up of 25 months was associated with a reduction in the combined outcome of cardiac death and non-fatal infarction providing there was no evidence of pulmonary congestion. In patients with pulmonary congestion, treatment with diltiazem was associated with an increase in the combined outcome of cardiac death and non- fatal infarction (1+).
6.6.1.4In a more recent randomised controlled trial of patients after MI without heart failure, treatment with diltiazem during 6 months of follow up, was associated with no significant reduction in the combination of cardiac death, non-fatal reinfarction or refractory ischaemia, although there was a reduction in the outcomes of non-fatal reinfarction and refractory ischaemia which was of borderline significance (1++).
6.6.1.5In a randomised controlled trial of patients with angiographically confirmed coronary artery disease (45% with previous MI), treatment with amlodipine was not associated with a reduction in progression of coronary atherosclerotic segments, although there was reduction in progression of carotid atherosclerosis. There was no significant effect on mortality, infarction or stroke (1+).
6.6.1.6Three randomised controlled trials with medium to long term follow up suggest that calcium channel blockers do not improve life expectancy compared with placebo in patients with heart failure who are already receiving an ACE inhibitor. Verapamil, diltiazem and short-acting dihydropyridines such as nifedipine can cause clinical deterioration. Amlodipine, a long-acting dihydropyridine, is not harmful in terms of adverse events (NICE Chronic Heart Failure guideline) (1++).
6.6.1.7Three non-UK studies found that treatment with calcium channel blockers compared to placebo in patients with angiographically documented CHD is cost effective.

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6.6.2. Clinical effectiveness of calcium channel blockers

6.6.2.1. Unselected patients

A meta analysis of 21 randomised controlled trials of unselected patients with a recent MI found that calcium channel blocker therapy was not associated with a reduction in mortality, although there was a reduction in non-fatal MI (OR 0.80, 95% CI 0.70 to 0.92, fixed effects, OR 0.81, 95% CI 0.69 to 0.96, random effects) (National Institute for Clinical Excellence 2001).

Two trials which were included in the meta analysis examined the interaction between diltiazem or verapamil treatment and whether or not patients had heart failure at baseline (Multicenter Diltiazem Postinfarction Trial Research Group. 1988) (Danish Study Group on Verapamil in Myocardial Infarction. 1990). In one trial treatment with diltiazem for an average of 25 months was not associated with a reduction in total mortality, death from cardiac causes, or non-fatal MI compared with placebo (Multicenter Diltiazem Postinfarction Trial Research Group. 1988). However subgroup analysis of the patient population found that in patients without pulmonary congestion, diltiazem was associated with a reduced number of cardiac events (death from cardiac causes, or non-fatal MI) (HR 0.77, 95% CI 0.61 to 0.98). In patients with pulmonary congestion, diltiazem was associated with an increased number of cardiac events (HR 1.41, 95% CI 1.01 to 1.96) (Multicenter Diltiazem Postinfarction Trial Research Group. 1988).

In a second trial, treatment with verapamil for an average of 16 months was not associated with a reduction in total mortality, cardiac death, or sudden death, compared with placebo, although there was a reduction in first reinfarction (HR 0.77, 95% CI 0.58 to 1.03) and the combination endpoint of first reinfarction or death (HR 0.80, 95% CI 0.66 to 0.99). However, in patients without heart failure immediately before randomisation, treatment with verapamil was associated with a reduction in total mortality, cardiac death, sudden death, first reinfarction or first cardiac event, whereas in patients with heart failure treatment with verapamil did not confer any benefit compared with placebo (Danish Study Group on Verapamil in Myocardial Infarction. 1990).

A more recent randomised controlled trial recruited patients after acute MI and excluded patients with CHF. In this trial, during 6 months of follow up, treatment with diltiazem compared with placebo had no effect on the cumulative first event rate of cardiac death, non-fatal reinfarction or refractory ischaemia (Boden, W. E. et al 2000) although there was a reduction in revascularisation, and the combination endpoint of non-fatal reinfarction or revascularisation (Boden, W. E., van Gilst, W. H., Scheldewaert, R. G. et al 2000).

A randomised controlled trial in patients with CAD, 45% with a prior MI, found that treatment with amlodipine compared with placebo had no effect on all-cause mortality, reinfarction, stroke, CHF or reduction in the progression of early atherosclerotic segments (Pitt, B. et al 2000). The primary objective of the study was to determine if treatment with amlodipine reduced the progression of early atherosclerotic segments detected on coronary angiography and the statistical power to detect a treatment difference in mortality and major morbidity was low. Treatment with amlodipine did reduce the progression of carotid artery atherosclerosis compared with placebo, and there were fewer cases of unstable angina (HR 0.67, 95% CI 0.48 to 0.93) and coronary revascularisation. Trial follow up was for 3 years (Pitt, B., Byington, R. P., Furberg, C. D. et al 2000).

The evidence for the secondary prevention effects of calcium channel blockers is not compelling, but the GDG felt that treatment with a rate limiting calcium channel blocker (diltiazem or verapamil) might be considered in patients not able to tolerate to a beta blocker, providing there were no signs of pulmonary congestion and left ventricular function was not impaired.

6.6.2.2. Patients with left ventricular dysfunction

No randomised controlled trials of the effectiveness of treatment with calcium channel blockers were identified which recruited patients with acute MI and left ventricular systolic dysfunction.

6.6.3. Health economics of calcium channel blockers

Three studies were found which met the inclusion criteria. None of the studies were done in the UK. All the studies used effectiveness data from the PREVENT study which examines the effectiveness of amlodipine compared with placebo in slowing the progression of early atherosclerosis in patients with angiographically documented CHD. The primary end point in the PREVENT was from the angiographic change, although clinical events were also monitored.

The first study (Casciano, R. et al 2002) assessed the cost effectiveness of amlodipine compared to placebo from a US third payer’s perspective. The use of amlodipine was effective in reducing hospitalisation and the episodes of revascularisation. The discounted costs/patient over the 3 years were less for amlodipine patients US$14 117 versus US$16 683 for placebo resulting in cost savings of about $2500. The estimated costs were robust in sensitivity analyses. They did a probabilistic simulation and in all cases amlodipine was the strategy of choice.

The second study (Cathomas, G. et al 2002) assessed the cost effectiveness of amlodipine compared to placebo from a Swiss healthcare perspective. There was no statistically significant difference in annual mortality However the adjusted life expectancy calculated using the all-cause mortality of the Swiss population similar to the PREVENT population resulted in 0.083 years gained due to amlodipine over the three years. The cost per life-year gained was Sfr 14 650 and the result was robust in sensitivity analysis.

The third study (Doyle, J. J. et al 2002) assessed the cost effectiveness of amlodipine compared to placebo from a Swedish healthcare perspective. Amlodipine was associated with fewer hospitalisations. Estimated costs per patient over the 3-year period were SEK 26 600 in the intervention group and SEK 27 400 in the control group. Thus, amlodipine was associated with cost-savings of SEK 800. The authors did not calculate the cost effectiveness ratio because amlodipine was dominant over placebo, that is, it was more effective and less costly. These findings were robust in both univariate and multivariate sensitivity analysis.

In conclusion, the calcium channel blocker, amlodipine compared to placebo in patients with angiographically documented CHD is cost effective. This conclusion is based on three non-UK studies, which were well conducted. However, the generalisability of the studies to post MI patients per se is not very clear since the patients recruited to the PREVENT study which was based on angiographic findings and in which the statistical power to detect a treatment difference in mortality and major morbidity was low.

6.7. Potassium channel activators

6.7.1. Evidence statement for potassium channel activators

6.7.1.1There is no significant reduction in CHD mortality or non-fatal MI in patients treated with nicorandil (1+).

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6.7.2. Clinical effectiveness of potassium channel activators

A systematic review identified one randomised controlled trial that compared nicorandil therapy versus placebo, although it was too small to provide evidence of benefit because only 70 patients were recruited (National Institute for Clinical Excellence 2001).

A more recent randomised controlled trial in 5126 patients with stable angina of which 66% had had a prior MI examined the effectiveness of nicorandil compared with placebo. Treatment with nicorandil resulted in a reduction of the composite primary outcome of CHD death, non-fatal MI, or unplanned hospital admission for cardiac chest pain compared with placebo (HR 0.83, 95% CI 0.72 to 0.97) (IONA Study Group 2002). However, the frequency of the secondary outcome of CHD death or non-fatal MI was similar in the two groups (IONA Study Group 2002) and there was no significant difference in all-cause mortality, CHD mortality and non-fatal MI. The combination of all cardiovascular events (defined as cardiovascular mortality, non-fatal MI, non-fatal stroke, hospital admission for transient ischaemic attack, and unplanned hospital admission for cardiac chest pain) (HR 0.86, 95% CI 0.86 to 0.98) and the combined endpoint of CHD death, non-fatal MI or unstable angina (HR 0.79, 95% CI 0.64 to 0.98) were reduced in the nicorandil group (IONA Study Group 2002).

6.8. Aldosterone antagonists in patients with heart failure and LV dysfunction

6.8.1. Evidence statements for aldosterone antagonists in patients with heart failure and LV dysfunction

6.8.1.1The only large trial of an aldosterone antagonist in early post MI patients with left ventricular systolic dysfunction (ejection fraction ≤ 40%) and clinical heart failure and or diabetes, showed that early treatment with eplerenone (initiated 3 to 14 days after acute MI), in addition to ACE inhibitors and beta blockers, reduced all-cause mortality, death from cardiovascular causes, sudden cardiac death, and episodes of heart failure. Patients with a serum creatinine concentration greater than 220 micromol/l and/or serum potassium greater than 5.0 mmol/l were excluded from the trial (1++).
6.8.1.2Treatment with aldosterone antagonist, eplerenone is cost effective, compared with placebo in patients early after MI with left ventricular systolic dysfunction.
6.8.1.3In one randomised controlled trial, initiation of spironolactone treatment in patients with chronic heart failure (of whom 54% had an ischaemic cause for heart failure) increased life expectancy and reduced the need for hospitalisation for cardiac causes (NICE Chronic Heart Failure guideline) (1++).

Back to recommendations

6.8.2. Clinical effectiveness of aldosterone antagonists

A randomised control trial examined the effectiveness of eplerenone in patients with left ventricular dysfunction following an MI. Trial inclusion required a left ventricular ejection fraction of ≤ 40% and also clinical signs of heart failure (90%) and / or diabetes (32%) (Pitt, B. et al 2003a). Eplerenone treatment was associated with reduced risk of the two primary endpoints: death from any cause (RR 0.85, 95% CI 0.75 to 0.96) and the combination of death from cardiovascular causes or hospitalisation for cardiovascular events (RR 0.87, 95% CI 0.79 to 0.95). There was also a lower risk of the following secondary endpoints: death from any cause or any hospitalisation (RR 0.92, 95% CI 0.86 to 0.98), death from cardiovascular causes (RR 0.83, 95% CI 0.72 to 0.94), sudden cardiac death (RR 0.79, 95% CI 0.64 to 0.97), and hospitalisation for heart failure (RR 0.85, 95% CI 0.74 to 0.99). Trial follow up was for a mean of 16 months (Pitt, B., Remme, W., Zannad, F. et al 2003a).

There was an increased risk of serious hyperkalemia in the eplerenone treated patients, while there was an increased risk of serious hypokalemia in the placebo group. Eplerenone treatment was also associated with an increase in the risk of gastrointestinal disorder. Patients in the placebo group reported a higher frequency of respiratory disorders (cough, dyspnea and pneumonia) and hypoglycaemia (Pitt, B., Remme, W., Zannad, F. et al 2003a).

No studies were found that considered how frequently patients with a prior MI treated with eplerenone should undergo testing of renal function and serum potassium.

A randomised controlled trial of the effectiveness of the aldosterone antagonist, spironolactone, in patients with chronic heart failure and left ventricular systolic dysfunction (of whom 54% had an ischaemic cause for heart failure), is examined in the NICE guideline Chronic Heart Failure: national clinical guideline for diagnosis and management in primary and secondary care, 2003 (National Collaborating Centre for Chronic Conditions. 2003). This guideline states that in patients with moderate to severe heart failure (NYHA Class III and IV) due to LV systolic dysfunction, the addition of low-dose spironolactone to therapy with a loop diuretic and ACE inhibitor (with and without digoxin) has been shown in a large randomised controlled trial to increase life expectancy when compared to placebo. In addition, hospitalisation for cardiac causes is greatly reduced.

The guideline group recognised that there was only one randomised controlled trial of eplerenone in the MI population, and its clinical effectivess has not been compared with a non selective aldosterone antagonist, spironolactone. No trial evidence was found on the clinical effectiveness of spironolactone in patients after an MI. In keeping with the available evidence, the GDG decided to recommend treatment with an aldosterone antagonist licensed for post-MI treatment (which is currently eplerenone) for patients who have had an acute MI and who have symptoms and/or signs of heart failure and left ventricular systolic dysfunction.

6.8.3. Health economics of aldosterone antagonists

Two studies were identified which examined the cost effectiveness of the aldosterone antagonist, eplerenone, compared with placebo in patients early after MI with left ventricular systolic dysfunction. Both studies used effectiveness data from the EPHESUS study (Pitt, B., Remme, W., Zannad, F. et al 2003a). From an economic perspective the correct comparison should be between eplerenone with the next best alternative, which in this case is spironolactone. Spironolactone is widely used in post MI patients but the GDG took the position that there was no direct effectiveness evidence of spironolactone in this patient group. This left us with epleronene compared with placebo as the the evidence base. Thus the summary of the two relevant studies that compared eplerenone with placebo in patients early after MI with left ventricular systolic dysfunction is given below.

The first analysis (Pfizer Ltd 2005) was done from the perspective of the Scottish NHS. It was well reported and concluded that eplerenone was cost effective as long as the NHS was willing to pay up to £9048/QALY gained. If the Scottish NHS was willing to pay £20 000 per additional QALY, there was a 92% probability that eplerenone was cost effective. The results were robust in sensitivity analysis.

The second study (Weintraub, W. S. et al 2005) used observational data from the Framingham, Saskatchewan and Worcester databases to extrapolate treatment effect beyond the EPHESUS trial observation period. The incremental cost effectiveness ratios were $21 072/QALY, $30 349 and $17 374/QALY using Framingham, Saskatchewan and Worcester data sources. These results were robust in sensitivity analyses. A probabilistic simulation showed that eplerenone was the optimal strategy in more than 87% for all ages and sexes at a threshold value of $50 000/QALY.

In conclusion eplerenone compared to placebo in patients early after MI with left ventricular systolic dysfunction and heart failure appears to be cost effective.

6.9. Lipid lowering agents

6.9.1. Evidence statements for lipid lowering agents

6.9.1.1In a meta analysis of 14 randomised controlled trials of secondary prevention in CHD, statin therapy was associated with a reduction in all- cause mortality, CVD mortality, CHD mortality, fatal MI, and coronary revascularisation compared with placebo (1++).
6.9.1.2In a systematic review of cohort studies, randomised trials, voluntary notifications to voluntary regulatory authorities and published case reports the incidence of adverse events was low. The estimate for rhabomyolysis was 3.4 per 100 000. However, the incidence of adverse events may be increased in patients treated with high dose statin, compared to low dose, and in patients treated with statins which are oxidised by cytochrome P450 3A4 (1++).
6.9.1.3There is conflicting evidence that fibrates reduce cardiovascular risk in patients after MI (1++).
6.9.1.4No studies were found testing the effectiveness of cholesterol absorption inhibitors for secondary prevention in patients after MI.

Back to recommendations

6.9.2. Clinical effectiveness of lipid lowering agents

The NICE Technology Appraisal (National Institute for Health & Clinical Excellence. 2006) entitled ‘Statins for the prevention of cardiovascular events’ 2006 states that:

Statin therapy is recommended for adults with clinical evidence of cardiovascular disease

The recommendation was based on the meta analysis of 14 randomised controlled trials of secondary prevention in CHD. Of these, four were conducted in MI and / or angina patients (Pedersen, T. R. et al 2004) (Sacks, F. M. et al 2000) (Liem, A. H. et al 2002) (Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. 1998). Four studies recruited patients with CAD (Pitt, B. et al 1995) (Crouse, J. R. et al 1995) (Jukema, J. W. et al 1995) (Teo, K. K. et al 2000), two studies recruited patients with CAD and hypercholesterolaemia (Bestehorn, H. P. et al 1997) (Riegger, G. et al 1999) one study recruited patients with mild CAD (Multicentre Anti-Atheroma Study (MAAS). 1994), two studies enrolled patients after coronary balloon angioplasty (Serruys, P. W. et al 1999) and (Bertrand, M. E. et al 1997), and one study enrolled patients after percutaneous coronary intervention (Serruys, P. W. et al 2002). Statin therapy was associated with a reduction in the following clinical outcomes compared with placebo: all-cause mortality (RR 0.79, 95% CI 0.70 to 0.90), CVD mortality (RR 0.75, 95% CI 0.68 to 0.83), CHD mortality (RR 0.72, 95% CI 0.64 to 0.80), fatal MI (RR 0.57, 95% CI 0.45 to 0.72), unstable angina (RR 0.82, 95% CI 0.72 to 0.94), hospitalisation for unstable angina (RR 0.90, 95% CI 0.70 to 0.90), non-fatal stroke (RR 0.75, 95% CI 0.59 to 0.95), new or worse intermittent claudication (RR 0.64, 95% CI 0.46 to 0.91) and coronary revascularisation (RR 0.77, 95% CI 0.69 to 0.85).

The NICE Technology Appraisal (National Institute for Health & Clinical Excellence. 2006) further states that:

The decision to initiate statin therapy should be made after an informed discussion between the responsible clinician and the individual about the risks and benefits of statin treatment, and taking into account additional factors such as comorbidity and life expectancy.

When the decision has been made to prescribe a statin, it is recommended that therapy should be initiated with a drug with a low acquisition cost (taking into account required daily dose and product price per dose).

6.9.2.1. Timing of statin therapy

No studies were identified that compared early statin with delayed statin therapy at the same dosage.

A randomised trial examined the effectiveness of early statin initiation in patients with acute coronary syndrome, in which 53% had had an acute non-Q wave MI (Olsson, A. G. et al 2005). This trial randomised patients to either high dose atorvastatin (80 mg daily) or placebo. Patients were hospitalised within 24 hours of the index event and randomised after a mean of 63 hours of hospitalisation. During or after hospitalisation for the index event, most were treated with aspirin, three quarters with beta blockers and half with ACE inhibitors or ARBs. The study period was for 16 weeks and during this period the primary end point (combination of death, non-fatal acute MI, cardiac arrest with resuscitation, or recurrent symptomatic myocardial ischemia with objective evidence requiring emergency rehospitalisation) was reduced in patients randomised to atorvastatin, compared to those randomised to placebo, a 16% relative risk reduction. There were no significant differences in the individual outcomes of death, non-fatal MI or cardiac arrest with resuscitation, although there was a lower risk of recurrent symptomatic myocardial ischaemia with objective evidence requiring emergency rehospitalisation in the group assigned to atorvastatin. Stroke was a secondary outcome with a significant lower incidence in the atorvastatin group. The reduction in the primary endpoint did not depend on the baseline level of LDL-cholesterol with similar risk reductions in those with a baseline LDL-cholesterol above or below the median. At the end of the study, compared to baseline, LDL-cholesterol had increased by an adjusted mean of 12% in the placebo group and had decreased by an adjusted mean of 40% in the atorvastatin group. More patients in the atorvastatin group developed liver transaminase levels more than 3 times the upper limit of normal. There were no cases of myositis (Olsson, A. G., Schwartz, G. G., Szarek, M. et al 2005).

A study has examined early use of statin therapy within the first 24 hours of admission for acute MI using data from the National Registry of Myocardial Infarction 4 (NRMI 4)(Fonarow, G. C. et al 2005). NRMI 4 is a prospective, observational database of consecutive patients admitted with acute MI to 1230 participating hospital throughout the United States. Data was collected on 300 823 patients. A total of 174 635 patients who had had an acute MI were included in the analysis. Of these, statin therapy was used in the first 24 hours of hopsitalisation in 39 096 patients (22.4%). There were 21 978 patients who were newly started on statin therapy and 17 118 patients who were continued on statin therapy. Statin therapy was discontinued in 9411 patients. There were 126 128 patients who did not receive statins before or within the first 24 hours of hospitalisation. New initiation of statin treatment within the first 24 hours of admission was associated with a decreased risk of in-hospital mortality compared with no statin use (4.0% versus 15.4%, respectively, adjusted OR 0.62, 95% CI 0.57 to 0.67). There was also a decreased risk of in-hospital mortality in patients who continued statin therapy compared with no statin usage (5.3% versus 15.4%, respectively, adjusted OR 0.58, 95% CI 0.54 to 0.63). In contrast, those patients that had been treated with statin therapy before hospitalisation but whose statin therapy had been discontinued had a slightly higher mortality risk compared with patients who did not use statins (16.5% versus 15.4%, respectively, adjusted OR 1.12, 95% CI 1.05 to 1.20). Early stain use, whether newly initiated or continued was also associated with a decreased incidence of cardiac arrest, cardiogenic shock, cardiac rupture, and ventricular tachycardia / ventricular fibrillation. There was no reduced risk of recurrent acute MI in patients treated with early statin therapy compared with no early statin usage (Fonarow, G. C., Wright, R. S., Spencer, F. A. et al 2005).

No randomised controlled trials were identified which examined concordance with statin treatment in patients treated before discharge compared to those treated later. However, the guideline group felt that initiation of statin treatment as soon as possible was likely to have a beneficial effect on concordance.

6.9.2.2. Adverse events

All randomised controlled trials which have examined the effectiveness of statin treatment excluded potential participants and a number of randomised controlled trials have also included a pre-randomisation run in phase during which participants were treated with an open label statin. At the end of this time some chose not to enter the trial or had some other reason not to do so, and were not randomised. Thus, tolerability may be better and the incidences of adverse events lower in the trials than in unselected patients. However, there are other sources of information which have helped inform the risk of adverse events.

In a systematic review of cohort studies, randomised trials, voluntary notifications to voluntary regulatory authorities and published case reports the incidence of rhabdomyolysis for statins other than cerivastatin was 3.4 (1.6 to 6.5) per 100 000 person years, with a case fatality of 10% (law, M. and Rudnicka, A. R. 2006). The incidence of rhabdomyolysis was higher (4.2 per 100 000 person years) with lovastatin, simvastatin or atorvastatin (which are oxidised by cytochrome P450 3A4 (CYP3A4) than with pravastatin or fluvastatin (which is not oxidised by CYP3A4). The rates were about 10 times higher for cerivastatin and also for statins other than cerivastatin when taken with gemfibrozil. For cervastatin taken with gemfibrozil, the incidence was 2 000 times higher, an absolute annual incidence of about 10%. The mean incidence of myopathy in patients treated with statins was 11 per 100 000 person years. There was no significant difference in the incidence of a raised creatine kinase to ≥ 10 fold the upper limit of normal on a single measurement during routine monitoring between participants in 13 trials allocated to a statin compared to those allocated placebo (83 per 100 000 person years of statin treatment versus 60 per 100,000 person years with placebo). In two trials, neither had CK elevated on 2 consecutive measurements (law, M. and Rudnicka, A. R. 2006).

The incidence of liver disease attributable to statin therapy is rare. In 3 randomised trials of pravastatin, both gall bladder and hepatobiliary disorders were less common in patients allocated statins than in those allocated placebo. In randomised trials elevations in alanine aminotransferase (ALT) and or aspartate aminotransferase (AST) were reported more frequently in patients treated with statins than with placebo, and elevations of ALT (defined as ≥ 3 times the ULN, or 120 U/L) were found in 300 statin-allocated and 200 placebo-allocated participants per 100 000 person-years. However, statistical heterogeneity across trials was noted. An elevated ALT on 2 consecutive measurements was found in 110 participants allocated to a statin and in 40 participants allocated to placebo per 100 000 person-years. Elevations in ALT were reported more frequently with higher doses of statin. The systematic review reported that in 100 000 person-years of statin use, denying 300 persons with elevated ALT the benefit of a statin (or 110 persons if repeat measures were used) would prevent liver disease in less than 1 person (law, M. and Rudnicka, A. R. 2006).

The guideline group noted that not treating patients with an elevated ALT prevents clinical liver disease in an extremely small number of patients. There was a consensus to recommend measurement of ALT or AST prior to starting statin treatment, so that in the event of an elevated level being found during statin treatment, it would be known if this had been present before initiation. However, patients with raised liver enzymes should not routinely be excluded from treatment with a statin (law, M. and Rudnicka, A. R. 2006).

Trials showed no excess of renal disease or proteinuria in statin allocated participants. There is evidence that statins cause peripheral neuropathy but the attributable risk is small (12 per 100 000 person years). No change in cognitive function was found in trials of statins in elderly patients (law, M. and Rudnicka, A. R. 2006).

6.9.3. Clinical effectiveness of fibrates, niacin and ezetimibe

A randomised controlled trial in patients with prior MI (≥6 months but <5 years before enrolment: 78%), and or stable angina pectoris compared treatment with the fibrate bezafibrate and placebo (Behar, S. et al 2000). Patients were followed up for mean of 6.2 years. Treatment with bezafibrate did not confer any benefit over placebo for the primary endpoint of the combination of fatal MI, non-fatal MI or sudden death. The overall incidence of any adverse event was 69% in both groups, and the frequency of adverse event was similar in both groups (Behar, S., Brunner, D., Kaplinsky, E. et al 2000).

In a further small randomised controlled trial in men aged less than 45 years with a prior MI 3 to 6 months earlier, treatment with bezafibrate, was associated with a reduction in the incidence of coronary events (reinfarction, CABG, PCI, sudden death or cardiovascular death) compared with placebo (de Faire, U. et al 1996). Concomitant drug therapy at the start of the trial was as follows: aspirin 11%, beta blockers 99%, long acting nitrates 27%, ACE inhibitors 0%. At follow up aspirin use had increased to 45% and ACE inhibitor therapy to 5%. Trial follow up was for 5 years. Total cholesterol and very low density lipoprotein cholesterol decreased in both groups, but to a significantly greater extent in the bezafibrate group. Triglyceride levels fell in the bezafibrate group, and increased in the placebo group. LDL- cholesterol did not change substantially in either group (de Faire, U., Ericsson, C. G., Grip, L. et al 1996).

A randomised controlled trial in patients with CAD (61% had a prior MI) recruited men with an HDL-cholesterol of 1.0mmol/l or less, LDL-cholesterol 3.6mmol/l or less and triglycerides less than 3.4 mmol/l (Rubins, H. B. et al 1999). At the start of the trial the majority of participants were taking aspirin, but less than half beta blockers and less than a quarter ACE inhibitors. Patients were randomised to either the fibrate gemfibrozil or placebo. Mean trial follow up was 5.1 years. Compared with placebo, gemfibrozil therapy was associated with a reduction in the primary endpoint (combination of non-fatal MI or death from CHD) (RR 0.78, 95% CI 0.65 to 0.93) and a reduction in the incidence of the secondary combination outcome of non-fatal MI, death from CHD or stroke (RR 0.76, 95% CI 0.64 to 0.89). Compared with placebo, gemfibrozil therapy was also associated with a reduction in non-fatal MI (RR 0.77, 95% CI 0.62 to 0.96) investigator-designated stroke (RR 0.81, 95% CI 0.52 to 0.98), transient ischaemic attack (RR 0.61, 95% CI 0.25 to 0.67), carotid endarterectomy (RR 0.55, 95% CI 0.40 to 0.78) and hospitalisation for CHF (RR 0.78, 95% CI 0.62 to 0.98), but, was not associated with a reduction in death due to CHD, death from any cause, confirmed stroke, CABG or PCI and hospitalisation for unstable angina. One year after randomisation, the mean total cholesterol level was 4% lower, the mean triglyceride level 31% lower and the mean HDL-cholesterol level 6% higher in patients assigned to gemfibrozil. Mean LDL-cholesterol levels were the same in both groups. Gemfibrozil treatment was associated with a greater incidence of dyspepsia (Rubins, H. B., Robins, S. J., Collins, D. et al 1999).

The GDG considered that while the trial evidence for fibrate treatment in patients after MI was contradictory, two studies did report evidence of benefit in cardiovascular outcomes (de Faire, U., Ericsson, C. G., Grip, L. et al 1996) (Rubins, H. B., Robins, S. J., Collins, D. et al 1999), and as such fibrates may be offered to those patients after MI who are intolerant of statins.

Treatment with niacin compared with placebo has been examined in a randomised controlled study in patients with a prior MI (Coronary Drug Project Research Group. 1975). This was an early study which randomly assigned patients with prior MI to six treatment groups; low and high conjugated oestrogen therapy, clofibrate, dextrothyroxine sodium, niacin and placebo. Niacin treatment was associated with a 9.9% reduction in total cholesterol from baseline and a 26.1% reduction in triglycerides (after correcting for changes in the placebo group). Compared with placebo, niacin treatment reduced the incidence of non-fatal MI (8.9% Niacin versus 12.2% placebo, Z = −2.88, P < 0.005) and also the combination of coronary death or non-fatal MI (22.8% Niacin versus 26.2% placebo, Z = −2.23, P < 0.01), but was not associated with a reduction in the incidence of the following outcomes: all-cause mortality, the individual components of all-cause mortality, definite pulmonary embolism (fatal or non-fatal), fatal or non-fatal stroke or intermittent cerebral ischaemic attack, definite or suspected fatal or non-fatal pulmonary embolism or thrombophlebitis and also any definite or suspected fatal or non-fatal cardiovascular event. Patients in the niacin group had a greater incidence of the following side effects compared with the placebo group: the combination of diarrhoea, nausea, vomiting, black tarry stools, stomach pain, flushing, itching of skin, urticaria, other type of rash, pain or burning when urinating, decrease in appetite, unexpected weight loss, and excessive sweating (Coronary Drug Project Research Group. 1975).

No randomised controlled trials were identified comparing the cholesterol absorption agent, ezetimibe with placebo in patients after MI.

6.9.4. Health economics of lipid lowering agents

6.9.4.1. Economics of statins

The latest HTA on statins was published in 2005 (National Institute for Health & Clinical Excellence. 2006). The HTA covered both primary and secondary prevention and was based on models of cost effectiveness. The guidance recommended statins with the lowest acquisition cost for people with clinical evidence of CVD and its recommendations will be adopted in this guideline. Further cost effectiveness analyses, including high versus standard dose statin treatment will underpin recommendations in the lipid modification guidelines.

6.9.4.2. Economics of fibrates

Only one study (Nyman, J. A. et al 2002) was found which met the inclusion criteria. This study used data from a single trial the US Department of Veterans Affairs (VA) Cooperative Studies Program HDL-C Intervention Trial (VA-HIT) (Rubins, H. B., Robins, S. J., Collins, D. et al 1999) which compared gemfibrozil with placebo. ICERs were estimated using two sets of prices for gemfibrozil. Using the prices of gemfibrozil that were negotiated by the VA, gemfibrozil was cost saving, while using prices found outside the VA, the ICERs ranged between $6300 and $17 100/QALY.

In conclusion, treatment with gemfibrozil was cost effective in a selected group of men with CHD with low levels of HDL-cholesterol and low levels of LDL-cholesterol. This finding was robust in sensitivity analysis. However the relevance to the general post MI population not selected on the basis of an initial lipid profile or by gender is not clear.

6.10. Monitoring guidance

Monitoring guidance

This section details the guidance for initiation, titration and monitoring of ACE inhibitors and epelenone treatment in patients after MI. The GDG considered that this specific information for these therapies was required in the post MI patient population.

Table 3Initiation, titration and monitoring of ACE inhibitors in patients after acute MI

Doses
ACE inhibitors should be started at an appropriate dose and titrated upwards until the optimum or target dose* is reached.
Which ACE inhibitor and target dose*
The doses are taken from the BNF for a post MI secondary prevention indication, the notes below indicate the specific licensed indication.
Licensed ACE inhibitor
Starting doseTarget dose
Captopril**6.25 mg tds50 mg tds
Lisinopril2.5 mg – 5 mg od10 mg od
Ramipril***1.25 – 2.5 mg bd5 mg bd
Trandalopril**0.5 mg od4 mg od
Enalapril****2.5 mg od20 mg od or 10 mg bd
These are the licensed recommended doses for post MI patients, and may differ from those for patients with symptomatic heart failure. In patients with asymptomatic LV systolic dysfunction aim for the target dose recommended in those with symptomatic heart failure and LV systolic dysfunction (refer to the NICE guidelines for chronic heart failure).
** licensed for use in patients following MI with left ventricular dysfunction.
*** licensed for use following myocardial infarction in patients with clinical evidence of heart failure and also susceptible patients over 55 years, prevention of MI, stroke, cardiovascular death or need of revascularisation procedures.
**** licensed for use in patients for prevention of symptomatic heart failure in patients with left ventricular dysfunction (this may include patients with MI in the past).
How to use
  • Avoid in patients with known severe renal artery stenosis.
  • Check renal function (creatinine) and serum electrolytes (particularly potassium), and blood pressure at baseline.
  • Seek specialist advice in patients taking a high dose loop diuretic (for example furosemide 80mg od) or if concerned about the risk of renal artery stenosis (for example if severe peripheral vascular disease).
  • Initiate a low dose of ACE inhibitor.
  • Titrate the dose of ACE inhibitor upwards at short intervals (for example every 1 to 2 weeks).
  • Monitor renal function (creatinine) and serum electrolytes, and blood pressure before starting an ACE inhibitor, again within 1 to 2 weeks of starting treatment. Monitor thereafter until treated with a stable dose, and then at least annually. More frequent monitoring should be considered in patients at risk of deterioration in renal function and or of developing hyperkalaemia, or during an intercurrent illness.
  • Aim for target dose, or maximum tolerated dose.
What to do if blood pressure is low
  • If asymptomatic, low blood pressure does not usually require any change in therapy.
  • If low blood pressure is symptomatic (dizziness, lightheadedness and or confusion), stop non-essential hypotensive agents (for example alpha blockers, diuretics if for hypertension and or if no signs of congestion).
  • If these measures do not resolve the problem seek specialist advice.
What to do with deteriorating renal function and hyperkalaemia
  • If serum creatinine is unchanged, continue to titrate upwards the ACE inhibitor, with monitoring of renal function (creatinine) and serum electrolytes, and blood pressure.
  • If serum creatinine increases > 30% from baseline, stop other potentially nephrotoxic drugs (for example NSAIDs), non-essential vasodilators (for example alpha blockers), and potassium retaining drugs (for example amiloride, triamterene), and if no signs of cardiac failure reduce dose of any diuretics. Consider seeking specialist advice.
  • Repeat after 1 week and if serum creatinine persistently increased > 30% from baseline, half the dose of ACE inhibitors, and if serum creatinine persistently > 30% above baseline, seek specialist advice.
  • If serum creatinine increases ≥50% from baseline, stop other potentially nephrotoxic drugs (for example NSAIDs), stop non-essential vasodilators (for example nitrates, alpha blockers), and potassium retaining drugs (for example amiloride, triamterene) and if no signs of congestion, reduce dose of any diuretics. Consider stopping the ACE inhibitor and or seeking specialist advice.
  • Repeat after 1 week and if serum creatinine persistently increased > 50% from baseline, stop the ACE inhibitor if still treated and seek specialist advice
  • If serum creatinine increases > 100% from baseline, or serum creatinine is > 350 micromol/l stop the ACE inhibitor and seek specialist advice.
  • A rise in serum potassium to ≤ 5.5 mmol/l is acceptable. If serum potassium rises to 5.6–5.9 mmol/l, review concomitant medication, and advice against the use of ‘lo-salt’ substitutes which may be high in potassium, repeat serum potassium after 1-2 weeks.
  • If serum potassium ≥6 mmol/l, stop the ACE inhibitor and seek specialist advice.
  • The rate of rise as well as the absolute level of serum potassium should be taken into account.
Adapted from the recommendations for monitoring ACE inhibitors in the NICE guidelines for the diagnosis and management of chronic heart failure in primary and secondary care , and part 2 of the renal National Serμvice Framework.

Table 4Initiation, titration and monitoring of aldosterone antagonists

Only one aldosterone antagonist is licensed for treatment of early post MI patients with heart failure at the time of issue of this guideline.
Eplerenone
Starting dose 25 mg, increasing to a maximum of 50 mg daily after 4 weeks (reduction in dose to 12.5 mg daily may be necessary if hyperkalaemia develops).
How to use
  • Check renal function and serum electrolytes.
  • Consider seeking specialist advice if concerned about an increased risk of developing serious hyperkalamia, for example in those with reduced renal function and or if baseline serum potassium is greater than 5 mmol/l.
  • Initiate eplerenone 25 mg daily.
  • Routinely measure blood biochemistry after 48 hours, 1 and 4 weeks, and 3 months, and 3 monthly thereafter, and 1 week after a titration upwards in the dose.
  • If serum potassium rises to between 5.5 and 5.9 mmol/l reduce dose of eplerenone by half (to 25 mg on alternate days, or 12.5 mg daily) and monitor closely.
  • The rate of rise as well as the absolute level of serum potassium should be taken into account.
  • If serum potassium rises to 6.0 mmol/l, stop eplerenone and seek specialist advice.
Other advice to patients
  • Avoid NSAIDs not prescribed by a physician (self-purchased ‘over the counter’ treatment, for example ibuprofen).
  • Temporarily stop eplerenone if diarrhoea and/or vomiting occurs and contact physician.
  • Some ‘low salt’ substitutes have a high potassium content and should be avoided.
Adapted from recommendations for monitoring the aldosterone antagonist, spironolactone, in the NICE guidelines for chronic heart failure and (Pitt, B. et al 2003b).

This recommendation is from NICE technology appraisal 80 (see section 6 for details), and has been incorporated into this guideline in line with NICE procedures for developing clinical guidelines.

The NICE clinical guideline ‘Cardiovascular risk assessment: the modification of blood lipids for the primary and secondary prevention of cardiovascular disease’ is in development and is expected to be published in January 2008. 3 The NICE clinical guideline ‘Cardiovascular risk assessment: the modification of blood lipids for the primary and secondary prevention of cardiovascular disease’ is in development and is expected to be published in December 2008.

Footnotes

1

This recommendation is from NICE technology appraisal 80 (see section 6 for details), and has been incorporated into this guideline in line with NICE procedures for developing clinical guidelines.

2

These drugs do not have UK marketing authorisation for this indication at the time of publication (March 2007) and specialist advice should be sought. Prescribers should check each drug’s Summary of product characteristics for current licensed indications

3

The NICE clinical guideline ‘Cardiovascular risk assessment: the modification of blood lipids for the primary and secondary prevention of cardiovascular disease’ is in development and is expected to be published in January 2008. 3 The NICE clinical guideline ‘Cardiovascular risk assessment: the modification of blood lipids for the primary and secondary prevention of cardiovascular disease’ is in development and is expected to be published in December 2008.

Copyright © 2007, National Collaborating Centre for Primary Care.
Bookshelf ID: NBK49337
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