Coronary Heart Disease

Figures derived from a 2022 Cochrane review¹.

• 68 studies including 80,702 patients
• published between 1975-2020
• mainly observational studies comparing smoking cessation with ongoing smoking

Reference

1)Wu AD, Lindson N, Hartmann-Boyce J et al. Smoking cessation for secondary prevention of cardiovascular disease. Cochrane Database of Systematic Reviews 2022, Issue 8. Art. No.: CD014936

The Cochrane reviewers rated this evidence as MODERATE quality¹:

• large number of studies at some risk of bias
• benefits consistent across studies with acceptable confidence intervals

Reference

1)Wu AD, Lindson N, Hartmann-Boyce J et al. Smoking cessation for secondary prevention of cardiovascular disease. Cochrane Database of Systematic Reviews 2022, Issue 8. Art. No.: CD014936

The population and trial characteristics in the Cochrane review¹ were very broad.

• studies from 1975-2020
• wide definitions of established CHD: acute events and stable disease
• wide definitions of smoking cessation and duration of follow up
• broad geographic spread of studies
• individual patient characteristics not summarised

Reference

1)Wu AD, Lindson N, Hartmann-Boyce J et al. Smoking cessation for secondary prevention of cardiovascular disease. Cochrane Database of Systematic Reviews 2022, Issue 8. Art. No.: CD014936

Figures derived from a 2019 Cochrane review¹ which found just one trial:

• Lyon Diet Heart Study²   published in 1999, included 605 patients
• compared Mediterranean Diet to usual care (“prudent diet”) in patients with established CHD

The NICE recommendation on Mediterranean diet has not been updated since 2007³.

References

1) Rees K, Takeda A, Martin N et al. Mediterranean‐style diet for the primary and secondary prevention of cardiovascular disease. Cochrane Database of Systematic Reviews 2019, Issue 3. Art. No.: CD009825

2) De Lorgeril M, Salen P, Martin JL et al. Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: Final report of the Lyon Diet Heart Study. Circulation 1999; 99(6): 779‐85

3)National Institute for Health and Care Excellence. Acute Coronary Syndromes 2020 [Internet]. [London]: NICE; 2020. (Clinical guideline [CG185])

Cochrane rated this evidence as LOW quality¹ due to:

• risk of bias resulting from
  • unclear randomisation
  • those allocated to the diet intervention had an opportunity to drop out of the study which the usual care group did not

However, the Cochrane authors highlight a large amount of observational research which links Mediterranean Diet with lower rates of cardiovascular disease.

Reference

1) Rees K, Takeda A, Martin N et al. Mediterranean‐style diet for the primary and secondary prevention of cardiovascular disease. Cochrane Database of Systematic Reviews 2019, Issue 3. Art. No.: CD009825

The population characteristics in the Lyon Diet Heart Study¹ were:

• mean age 54
• 10% female
• ethnicity not reported
• all with MI in last 6 months
• 62% smokers
• exclusions: uncontrolled hypertension or angina, heart failure NYHA Stage III or IV

Reference

1)De Lorgeril M, Salen P, Martin JL et al. Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: Final report of the Lyon Diet Heart Study. Circulation 1999; 99(6): 779‐85

Figures derived from from a 2021 Cochrane review^{1 :}

• 79 studies including 23,430 patients
• compared exercise-based cardiac rehabilitation programmes to usual care

Reference

Dibben G, Faulkner J, Oldridge N et al. Exercise‐based cardiac rehabilitation for coronary heart disease. Cochrane Database of Systematic Reviews 2021, Issue 11. Art. No.: CD001800

The Cochrane reviewers rated this evidence as HIGH quality¹.

• randomised controlled trials without major risk of bias
• relevant to a broad population with CHD
• consistent effects demonstrated with reasonable confidence intervals

Data detail

The evidence regarding hospital admissions was rated as MODERATE quality due to possible publication bias.

References

1)Dibben G, Faulkner J, Oldridge N et al. Exercise‐based cardiac rehabilitation for coronary heart disease. Cochrane Database of Systematic Reviews 2021, Issue 11. Art. No.: CD001800

The population characteristics in the Cochrane review were very broad. Of the trials analysed:

• 48 were from Europe, 16 were from low or middle income countries.
• half involved patients post-MI only, the rest were mixed CHD (angina, post MI/PCI/CABG)
• median age range in trials 44-77
• 18% female

Neither NICE¹ nor Cochrane² were able to highlight a particular group of patients or mode of rehabilitation which appears to have better or worse outcomes.

References

1)National Institute for Health and Care Excellence. Acute Coronary Syndromes 2020 [Internet]. [London]: NICE; 2020. (Clinical guideline [CG185])

2)Dibben G, Faulkner J, Oldridge N et al. Exercise‐based cardiac rehabilitation for coronary heart disease. Cochrane Database of Systematic Reviews 2021, Issue 11. Art. No.: CD001800

Quality of life scores were measured by some studies:

• Only marginal gains were demonstrated in the short term (1 year follow-up).

Reference

Dibben G, Faulkner J, Oldridge N et al. Exercise‐based cardiac rehabilitation for coronary heart disease. Cochrane Database of Systematic Reviews 2021, Issue 11. Art. No.: CD001800

Aspirin v placebo

Figures derived from a 2009 systematic review¹:

• 6 trials of aspirin vs placebo included 10,859 patients with a history of previous MI
• trials conducted from 1970s-1990s

Clopidogrel+aspirin v aspirin alone

Figures derived from the 2001 CURE study²:

• included 12,562 patients with recent NSTEMI
• chosen as the most applicable study from a 2017 Cochrane review³ which included 13 studies

Ticagrelor and prasugrel

The evidence review for the 2020 NICE guideline⁴ explored the complex evidence base for these drugs.

• included 28 studies comparing these two drugs to clopidogrel or each other in combination with aspirin following acute coronary syndrome (ACS)

• The studies were highly varied in terms of type of ACS and other treatments (e.g., revascularisation or no revascularisation), so there is no single data set which provides an overall estimate of their benefits and harms.

References

1)Antithrombotic Trialists’ (ATT) Collaboration. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. The Lancet 2009; 373(9678): 1849-1860

2)CURE Investigators. Effects of Clopidogrel in Addition to Aspirin in Patients with Acute Coronary Syndromes without ST-Segment Elevation. N Engl J Med 2001; 345: 494-502

3) Squizzato A, Bellesini M, Takeda A et al. Clopidogrel plus aspirin versus aspirin alone for preventing cardiovascular events. Cochrane Database of Systematic Reviews 2017, Issue 12. Art. No.: CD005158

4)National Institute for Health and Care Excellence. Acute Coronary Syndromes 2020 [Internet]. [London]: NICE; 2020 (Clinical guideline [CG185]).

The evidence for both aspirin and clopidogrel is MODERATE quality:

• randomised controlled trials with large numbers of patients
• statistically significant outcomes with reasonable confidence intervals
• results are applicable to primary care population

However,

• some risk of bias in the aspirin v placebo trials
• some risk of publication bias in the clopidogrel trials

NICE rates the evidence for ticagrelor and prasugrel as LOW quality for a variety of reasons.

References

1)Antithrombotic Trialists’ (ATT) Collaboration. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009; 373(9678): 1849-1860

2)CURE Investigators. Effects of Clopidogrel in Addition to Aspirin in Patients with Acute Coronary Syndromes without ST-Segment Elevation. N Engl J Med 2001; 345:494-502

3) Squizzato A, Bellesini M, Takeda A et al. Clopidogrel plus aspirin versus aspirin alone for preventing cardiovascular events. Cochrane Database of Systematic Reviews 2017, Issue 12. Art. No.: CD005158

4)National Institute for Health and Care Excellence. Acute Coronary Syndromes 2020 [Internet]. [London]: NICE; 2020 (Clinical guideline [CG185])

The population characteristics in the aspirin vs placebo analyses were not reported¹.

The population characteristics in the CURE study² (clopidogrel+aspirin vs aspirin alone) were:

• mean age 64
• 38% female
• ethnicity not reported
• acute unstable angina or NSTEMI
• 1/3 with previous MI, 18% previous CABG
• 4% previous stroke
• 7% heart failure
• 23% diabetes
• 61%  current or ex-smokers

References

1)Antithrombotic Trialists’ (ATT) Collaboration. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009; 373(9678): 1849-1860

2)CURE Investigators. Effects of Clopidogrel in Addition to Aspirin in Patients with Acute Coronary Syndromes without ST-Segment Elevation. N Engl J Med 2001; 345: 494-502

Many patients have a dual indication for antiplatelets and oral anticoagulants.

Current evidence is not clear enough to provide good estimates of benefit or bleeding risk for the variety of situations we may encounter.

For patients with atrial fibrillation and stable ischaemic heart disease (say, an MI more than one year ago):

• An oral anticoagulant alone probably provides equal protection from recurrent MI and stroke as compared to combined therapy^1,2.
• Combined therapy increases bleeding risk.
• NICE recommend an individualised approach³:
  • For people with an ongoing indication for anticoagulation 12 months after an MI, take into consideration all of the following when thinking about the need for continuing antiplatelet therapy:
    • indication for anticoagulation
    • bleeding risk
    • thromboembolic risk
    • cardiovascular risk
    • person’s wishes

For patients with more complex needs (e.g., after coronary artery stent insertion, who may need dual antiplatelet therapy in addition to an oral anticoagulant) the evidence is complex:

• NICE recommend an individualised approach.
• This decision will usually be made in secondary care.
• Co-prescribing of dual antiplatelet therapy and oral anticoagulants is associated with high rates of major bleeding – up to 10% over 1 year⁴.
• However, this risk is weighed against high risks of stent obstruction and its associated mortality.

References

1)2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. European Heart Journal 2021 Feb 1; 42(5): 373-498

2)Lemesle G. Aspirin on Top of Anticoagulation in Patients With Concomitant Stable Coronary Artery Disease and Atrial Fibrillation. Circulation 2019; 139: 617–619

3)National Institute for Health and Care Excellence. Acute Coronary Syndromes 2020 [Internet]. [London]: NICE; 2020 (Clinical guideline [CG185])

4)MASTER DAPT Investigators. Abbreviated Antiplatelet Therapy in Patients at High Bleeding Risk With or Without Oral Anticoagulant Therapy After Coronary Stenting: An Open-Label, Randomized, Controlled Trial. Circulation 2021 Oct 12; 144(15): 1196-1211

The figure of a 40% RRR (relative risk reduction) for atorvastatin 80mg was estimated from the evidence review for the 2014 NICE guideline on lipid modification¹.

The figures for cardiovascular event rates with “No treatment” are from a meta-analysis which pooled data from 5 trials of statin v placebo in patients with established CHD.²

The recommendations for second-line lipid lowering agents were made in an update to the NICE guideline in December 2023.

References

1)National Institute for Health and Care Excellence. Cardiovascular disease: Risk Assessment and reduction, including lipid modification 2014 [Internet]. [London]: NICE; 2014 [updated 2016 Sep]. (Clinical guideline [CG181])

2)Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins. Lancet 2005; 366(9493): 1267-1278

The population characteristics in the statin secondary prevention trials were:

• age range 21-75
• roughly 10% female
• ethnicity not recorded
• all with previous CHD
• roughly 5% with diabetes

Reference

1)Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins. Lancet 2005; 366(9493): 1267-1278

An increasing benefit from higher intensity statins was found in the overall NICE evidence review for cardiovascular risk reduction¹.

However, there is no direct trial comparison of atorvastatin 80mg v (say) atorvastatin 20mg in post-MI patients.

The recommendation for atorvastatin 80mg was a NICE committee decision¹.

• See the Statins in primary prevention (high v low dose) section for more details and estimates of benefit for different intensity statins.

Reference

1)National Institute for Health and Care Excellence. Cardiovascular disease: Risk Assessment and reduction, including lipid modification 2014 [Internet]. [London]: NICE; 2014 [updated 2016 Sep]. (Clinical guideline [CG181])

Figures derived from a 2021 Cochrane review¹ which included

• 25 trials involved 22,423 patients
• 24 trials were conducted before 1999, many in the 1980s
• beta-blockers were commenced in the non-acute or stable phase post-MI

Reference

1)Safi S, Sethi NJ, Korang SK et al. Beta‐blockers in patients without heart failure after myocardial infarction. Cochrane Database of Systematic Reviews 2021, Issue 11. Art. No.: CD012565

Cochrane rated this evidence as LOW – VERY LOW quality¹ because:

• most trials at high risk of bias (various flaws in methods or reporting)
• most trials conducted in the “pre-reperfusion” era and therefore may not be applicable to a modern setting

Reference

1)Safi S, Sethi NJ, Korang SK et al. Beta‐blockers in patients without heart failure after myocardial infarction. Cochrane Database of Systematic Reviews 2021, Issue 11. Art. No.: CD012565

Note: the Cochrane reviewers rated the evidence as MODERATE – LOW quality but did not account for the poor applicability of the evidence to the modern era, so the quality rating has been downgraded one step further here.

The Cochrane review¹ selected trials where:

• beta-blockers were started in the non-acute/stable phase post MI
• most patients did not have heart failure or LVSD
  • however, many trials would likely have included some patients with HF or LVSD because routine echocardiography was not in use as at the time

Limited information is available on the participants’ characteristics:

• mean age 57 (50-63)
• 17% female
• most trials were international/multi-centre

Reference

1)Safi S, Sethi NJ, Korang SK et al. Beta‐blockers in patients without heart failure after myocardial infarction. Cochrane Database of Systematic Reviews 2021, Issue 11. Art. No.: CD012565

Beta-blockers can control anginal symptoms but do not have a prognostic benefit in stable angina in the way they may do post-MI.

NICE recommends considering either a beta-blocker or calcium channel blocker as first-line treatment¹.

• NICE’s evidence review (last updated 2016) referred to a 2012 systematic review² of 89 RCTs (including 21,674 patients) 
  • no benefit found on mortality for beta-blockers compared to other anti-anginal agents or placebo

References

1)National Institute for Health and Care Excellence. Management of Stable Angina [Internet]. [London]: NICE; 2016 (Clinical guideline [CG126])

2)Huang HL, Fox KA. The impact of beta-blockers on mortality in stable angina: a meta-analysis. Scottish Medical Journal 2012; 57: 69–75

Beta-blockers are safe to use for CHD with these co-morbidities¹:

• COPD
  • no adverse effect on FEV1 or respiratory symptoms²
• Peripheral Vascular Disease
  • no adverse affect on walking capacity or symptoms of intermittent claudication in patients with mild to moderate peripheral arterial disease³
• Diabetes
  • may cause a small increase plasma glucose levels, but the benefits of treatment in the first year post-MI are likely to outweigh any potential harms
  •  a 2015 systematic review found limited LOW quality evidence from small, short term trials⁴ showing:
    • 1.33 mmol/L increase in fasting plasma glucose with non-selective beta-blockers (including carvedilol)
    • no increase in fasting plasma glucose with cardioselective beta-blockers (atenolol and nebivolol). Bisoprolol is cardioselective but was not studied in this review

Caution is needed in asthma (or reversible airways disease) as beta-blockers can induce bronchospasm.

• However, cardioselective beta-blockers may well be safe for most.
• Initiate cardioselective beta-blocker under specialist supervision for those with asthma and HF-REF (Source BNF).
  • A 2002 Cochrane review⁵ of small, short term randomised trials of cardioselective beta-blockers in patients with stable, mild-moderate, reversible airways disease showed no adverse respiratory effects.
  • A 2021 review⁶ of observational data and global safety reports found no evidence of asthma exacerbations or death associated with cardioselective beta-blockers.

References

1)Chronic Heart Failure: National Clinical Guideline for Diagnosis and Management in Primary and Secondary Care: Partial Update [Internet]. London: Royal College of Physicians (UK); 2010 Aug. (NICE Clinical Guidelines, No. 108.) 4, Diagnosing heart failure

2)Salpeter SR, Ormiston TM, Salpeter EE. Cardioselective beta‐blockers for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2005, Issue 4. Art. No.: CD003566

3)Radack K, Deck C. Beta-adrenergic blocker therapy does not worsen intermittent claudication in subjects with peripheral arterial disease. A meta-analysis of randomized controlled trials. Arch Intern Med 1991 Sep; 151(9): 1769-76

4)Hirst JA, Farmer AJ, Feakins BG et al. Quantifying the effects of diuretics and β-adrenoceptor blockers on glycaemic control in diabetes mellitus – a systematic review and meta-analysis. British Journal of Clinical Pharmacology 2015; 79(5): 733–743

5)Salpeter SR, Ormiston TM, Salpeter EE, Wood‐Baker R. Cardioselective beta‐blockers for reversible airway disease. Cochrane Database of Systematic Reviews 2002, Issue 4. Art. No.: CD002992

6)Bennett B, Chang C, Tatley M et al. The safety of cardioselective β₁-blockers in asthma: literature review and search of global pharmacovigilance safety reports. ERJ Open Research Jan 2021;  7(1): 00801-2020

Figures derived from a key trial (EUROPA)¹ which formed part of the 2013 NICE evidence review².

The NICE review drew mainly on 2 very similar trials with similar results (the other study was HOPE³).

We have presented the EUROPA results as they are slightly more applicable to current practice (see Study Population for more details).

• EUROPA compared perindopril 8mg with placebo
• involved 12,218 patients

References

1)National Institute for Health and Care Excellence. MI – Secondary Prevention Partial Update[Internet]. [London]: NICE; 2013. (Clinical guideline [CG48])

2)The EUROPA Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet 2003; 362(9386): 782-788

3)The HOPE Investigators. Effects of an Angiotensin-Converting–Enzyme Inhibitor, Ramipril, on Cardiovascular Events in High-Risk Patients. N Engl J Med 2000; 342: 145-153

NICE rated this evidence as MODERATE quality¹:

• large randomised controlled trials
• at low risk of bias
• significant effects demonstrated with reasonable confidence intervals

However,

• roughly 1/3 of the EUROPA trial patients had not had a previous MI

Reference

1)National Institute for Health and Care Excellence. MI – Secondary Prevention [Internet]. [London]: NICE; 2013 (Clinical guideline [CG48])

The characteristics of participants in the EUROPA trial were¹:

• mean age 60
• 15% female
• ethnicity not reported
• 64% previous MI, 55% previous revascularisation
• 12% diabetes
• 27% hypertension
• 3% previous stroke/TIA
• 92% on antiplatelets
• 61% on beta-blockers
• 58% on lipid-lowering therapy
• mean BP 137/82mmHg

Reference

1)The EUROPA Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet 2003; 362(9386): 782-788

Angiotensin Receptor Blockers (ARBs) appear to be as effective as ACE inhibitors in preventing future vascular events and mortality in a post-MI population.

The NICE evidence review in 2013¹ found 1 trial² involving:

• 17,118 people at high risk of CVD
• half had a history of MI
• telmisartan 80mg v ramipril 10mg
• 5-year follow-up
• no difference in outcomes between groups

LOW-MODERATE quality evidence:

• only 50% of population studied had a previous MI
• possible risk of bias from randomisation procedures

References

1)National Institute for Health and Care Excellence. MI – Secondary Prevention [Internet]. [London]: NICE; 2013 (Clinical guideline [CG48])

2)The ONTARGET Investigators. Telmisartan, Ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008; 358: 1547-1559