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BMJ Clin Evid. 2006; 2006: 0601.
Published online 2006 February 1.
PMCID: PMC2907631

Diabetes: prevention of cardiovascular events

Ronald J Sigal, MD MPH FRCPC, Associate Professor of Medicine and Human Kinetics,# Janine C Malcolm, MD FRCP(C), Clinical Scholar, Division of Endocrinology and Metabolism,# and Amel Arnaout#

Abstract

Introduction

Diabetes mellitus is a major risk factor for cardiovascular disease. In the USA, a survey of deaths in 1986 suggested that 60−75% of people with diabetes die from cardiovascular causes.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of promoting smoking cessation; controlling blood pressure; treating dyslipidaemia; blood glucose control; treating multiple risk factors; revascularisation procedures; and antiplatelet drugs in people with diabetes? We searched: Medline, Embase, The Cochrane Library and other important databases up to November 2004 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 63 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: antihypertensive drugs, antihypertensive treatment, aspirin, clopidogrel, coronary artery bypass graft, diet, fibrates, glycaemic control (intensive versus conventional control), heparin (with or without glycoprotein IIb/IIIa inhibitors, or clopidogrel), lower target blood pressures, metformin, multiple risk factor treatment (intensive), percutaneous transluminal coronary angioplasty (plus stent), smoking cessation, statins (aggressive or moderate lipid lowering, low or standard dose), stent (plus glycoprotein IIb/IIIa inhibitors), thrombolysis.

Key Points

People with diabetes mellitus have 2−4 times the risk of cardiovascular disease, and are up to 3 times more likely to die after a myocardial infarction, compared with normoglycaemic people.

Intensive treatment of multiple risk factors in people with type 2 diabetes and microalbuminuria reduces the risk of cardiovascular disease compared with conventional treatment.

  • Promotion of smoking cessation is likely to reduce cardiovascular events in people with diabetes, although no studies have specifically studied this.

Tight control of blood pressure and reduction of cholesterol reduces the risk of cardiovascular events in people with hypertension and diabetes.

  • Angiotensin converting enzyme inhibitors, angiotensin receptor antagonists, beta-blockers, calcium channel blockers and diuretics have all been shown to have similar antihypertensive effects.
  • Reduction of cholesterol with statins reduces cardiovascular morbidity and mortality in people with diabetes regardless of initial cholesterol levels, and fibrates may also be beneficial.
  • Aspirin and clopidogrel have not been consistently shown to reduce cardiovascular events or mortality in people with diabetes and cardiovascular disease compared with controls, and increase the risk of bleeding.
  • Intensive blood glucose control reduces the risk of cardiovascular events in people with type 1 diabetes, but has not been consistently shown to reduce cardiovascular morbidity or mortality in people with type 2 diabetes.

Coronary artery bypass grafts reduce 4 year mortality compared with percutaneous transluminal coronary angioplasty (PTCA) in people with diabetes, although longer term benefits are unclear.

  • PTCA may reduce short term mortality or myocardial infarction compared with thrombolysis in people with diabetes and acute myocardial infarction.
  • Adding glycoprotein IIb/IIIa inhibitors reduces cardiovascular morbidity and mortality compared with placebo in people with acute coronary syndrome or undergoing PTCA plus stenting.

About this condition

Definition

Diabetes mellitus: Diabetes mellitus is a group of disorders characterised by hyperglycaemia, defined as a fasting plasma glucose ≥ 7.0 mmol/L or ≥ 11.1 mmol/L 2 hours after a 75 g oral glucose load, on two or more occasions. Intensive treatment is designed to achieve blood glucose values as close to the non-diabetic range as possible. The components of such treatment are education, counselling, monitoring, self management, and pharmacological treatment with insulin or oral anti-diabetic agents to achieve specific glycaemic goals. Cardiovascular disease: Atherosclerotic disease of the heart and/or the coronary, cerebral, or peripheral vessels leading to clinical events such as acute myocardial infarction, congestive heart failure, sudden cardiac death, stroke, gangrene, and/or need for revascularisation procedures. Population: In previous versions of BMJ Clinical Evidence, we attempted to differentiate between primary and secondary prevention in this review. However, in middle aged and older people with type 2 diabetes, this distinction may not be clinically important. We are not aware of any intervention that has been shown to be effective in secondary prevention but ineffective in primary prevention, or vice versa, in people with diabetes. In most cases, a large proportion of people with diabetes entered into cardiovascular disease prevention trials are middle aged and older, with additional cardiovascular risk factors, and a large portion of these actually have undiagnosed cardiovascular disease.

Incidence/ Prevalence

Diabetes mellitus is a major risk factor for cardiovascular disease. In the USA, a survey of deaths in 1986 suggested that 60−75% of people with diabetes die from cardiovascular causes. The annual incidence of cardiovascular disease is increased in people with diabetes (men: RR 2−3; women: RR 3−4, adjusted for age and other cardiovascular risk factors). About 45% of middle aged and older white people with diabetes have evidence of coronary artery disease compared with about 25% of people without diabetes in the same populations. In a Finnish population based cohort study (1059 people with diabetes and 1373 people without diabetes, aged 45−64 years), the 7 year risk of acute myocardial infarction was as high in adults with diabetes without previous cardiac disease (20.2/100 person years) as it was in people without diabetes with previous cardiac disease (18.8/100 person years).

Aetiology/ Risk factors

Diabetes mellitus increases the risk of cardiovascular disease. Cardiovascular risk factors in people with diabetes include conventional risk factors (age, prior cardiovascular disease, cigarette smoking, hypertension, dyslipidaemia, sedentary lifestyle, family history of premature cardiovascular disease) and more diabetes specific risk factors (elevated urinary protein excretion, poor glycaemic control). Conventional risk factors for cardiovascular disease contribute to an increase in the relative risk of cardiovascular disease in people with diabetes to about the same extent as in those without diabetes. One prospective cohort study (164 women and 235 men with diabetes [mean age 65 years] and 437 women and 1099 men without diabetes [mean age 61 years] followed for mortality for a mean of 3.7 years after acute myocardial infarction) found that significantly more people with diabetes died compared with people without diabetes (116/399 [29%] with diabetes v 204/1536 [13%] without diabetes; RR 2.2, 95% CI 1.8 to 2.7). It also found that the mortality risk after myocardial infarction associated with diabetes was higher for women than for men (adjusted HR 2.7, 95% CI 1.8 to 4.2 for women v 1.3, 95% CI 1.0 to 1.8 for men). Physical inactivity is a considerable risk factor for cardiovascular events in both men and women. Another cohort study (5125 women with diabetes) found that participation in little (< 1 hour a week) or no physical activity compared with physical activity for at least 7 hours a week was associated with a doubling of the risk of a cardiovascular event. A third cohort study (1263 men with diabetes, mean follow up 12 years) found that low baseline cardiorespiratory fitness increased overall mortality compared with moderate or high fitness (RR 2.9, 95% CI 2.1 to 3.6), and overall mortality was higher in those reporting no recreational exercise in the previous 3 months than in those reporting any recreational physical activity in the same period (RR 1.8, 95% CI 1.3 to 2.5). The absolute risk of cardiovascular disease is almost the same in women as in men with diabetes. Diabetes specific cardiovascular risk factors include the duration of diabetes during adulthood (the years of exposure to diabetes before age 20 years add little to the risk of cardiovascular disease); raised blood glucose concentrations (reflected in fasting blood glucose or HbA1c); and any degree of microalbuminuria (albuminuria 30−299 mg/24 hours). People with diabetes and microalbuminuria have a higher risk of coronary morbidity and mortality than people with normal levels of urinary albumin and a similar duration of diabetes (RR 2−3). Clinical proteinuria increases the risk of mortality from cardiac events in people with type 2 diabetes (RR 2.61, 95% CI 1.99 to 3.43) and type 1 diabetes (RR 9) compared with people with the same type of diabetes who have normal albumin excretion. An epidemiological analysis of people with diabetes enrolled in the Heart Outcomes Prevention Evaluation cohort study (3498 people with diabetes and at least 1 other cardiovascular risk factor, age > 55 years, of whom 1140 [32%] had microalbuminuria at baseline; 5 years follow up) found a higher risk for major cardiovascular events in those with microalbuminuria (albumin : creatinine ratio [ACR] ≥ 2.0 mg/mmol) than in those without microalbuminuria (adjusted RR 1.97, 95% CI 1.68 to 2.31), and for all cause mortality (RR 2.15, 95% CI 1.78 to 2.60). It also found an association between ACR and the risk of major cardiovascular events (ACR 0.22−0.57 mg/mmol: RR 0.85, 95% CI 0.63 to 1.14; ACR 0.58−1.62 mg/mmol: RR 1.11, 95% CI 0.86 to 1.43; ACR 1.62−1.99 mg/mmol: RR 1.89, 95% CI 1.52 to 2.36).

Prognosis

Diabetes mellitus increases the risk of mortality or serious morbidity after a coronary event (RR 1.5−3.0). This excess risk is partly accounted for by increased prevalence of other cardiovascular risk factors in people with diabetes. A systematic review (search date 1998, 15 prospective cohort studies) found that, in people with diabetes admitted to hospital for acute myocardial infarction, "stress hyperglycaemia" was associated with significantly higher mortality in hospital compared with lower blood glucose levels (RR 1.7, 95% CI 1.2 to 2.4). One large prospective cohort study (91 285 men aged 40−84 years) found that, compared with men with no diabetes and no coronary heart disease (CHD), there was higher all cause and CHD mortality at 5 years' follow up in men with diabetes with or without CHD, in men with coronary artery disease alone, with the highest risk in men with both risk factors, see table 1 ). Multivariate analysis did not materially alter these associations. Diabetes mellitus alone is associated with a twofold increase in risk for all cause death, with a threefold increase in risk of death from CHD, and, in people with pre-existing CHD, with a 12-fold increase in risk of death from CHD compared with people with neither risk factor.

Table 1
Diabetes and all cause mortality and coronary heart disease mortality in US physicians

Aims of intervention

To reduce mortality and morbidity from cardiovascular disease with minimum adverse effects.

Outcomes

Incidence of fatal or non-fatal acute myocardial infarction; congestive heart failure; sudden cardiac death; coronary revascularisation; stroke; gangrene; angiographic evidence of coronary, cerebral, vascular, or peripheral arterial stenosis; all cause mortality.

Methods

Clinical Evidence search and appraisal November 2004. We searched for systematic reviews and RCTs with at least 10 confirmed clinical cardiovascular events among people with diabetes. Studies reporting only intermediate end points (e.g. regression of plaque on angiography, lipid changes) were not included. Most of the evidence comes from subgroup analyses of large RCTs that included people with diabetes. As with all subgroup analyses, and studies with small numbers, these results must be interpreted as suggestive rather than definitive. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ).

Table
GRADE evaluation of interventions for prevention of cardiovascular events in diabetes

Glossary

Acute myocardial infarction
is infarction that occurs when circulation to a region of the heart is obstructed and necrosis is occurring; clinical symptoms include severe pain, pallor, perspiration, nausea, dyspnoea, and dizziness. Myocardial infarction is gross necrosis of the myocardium as a result of interruption of the blood supply, usually caused by atherosclerosis of the coronary arteries; myocardial infarction without pain or other symptoms (silent infarction) is common in people with diabetes.
HbA1c
The haemoglobin A1c test is the most common laboratory test of glycated haemoglobin (haemoglobin that has glucose irreversibly bound to it). HbA1c provides an indication of the “average” blood glucose over the preceding 3 months. The HbA1c is a weighted average over time of the blood glucose level; many different glucose profiles can produce the same level of HbA1c
High-quality evidence
Further research is very unlikely to change our confidence in the estimate of effect.
Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Notes

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients.To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.

Notes

Diabetes: managing dyslipidaemia

Diabetes: treating hypertension

Contributor Information

Ronald J Sigal, Clinical Epidemiology Program, Ottawa Hospital, Ottawa, Canada.

Janine C Malcolm, University of Ottawa, Ottawa, Canada.

Amel Arnaout, University of Ottawa, Ottawa Hospital, Ottawa, Canada.

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76. Kleiman NS, Lincoff AM, Kereiakes DJ, et al. Diabetes mellitus, glycoprotein IIb/IIIa blockade, and heparin: evidence for a complex interaction in a multicenter trial. EPILOG Investigators. Circulation 1998;97:1912−1920. [PubMed]
77. Marso SP, Lincoff AM, Ellis SG, et al. Optimizing the percutaneous interventional outcomes for patients with diabetes mellitus: results of the EPISTENT (Evaluation of platelet IIb/IIIa inhibitor for stenting trial) diabetic substudy. Circulation 1999;100:2477−2484. [PubMed]
78. The EPISTENT Investigators. Randomised placebo-controlled and balloon-angioplasty-controlled trial to assess safety of coronary stenting with use of platelet glycoprotein-IIb/IIIa blockade. Evaluation of platelet IIb/IIIa inhibitor for stenting. Lancet 1998;352:87−92. [PubMed]
79. Topol EJ, Mark DB, Lincoff AM, et al. Outcomes at 1 year and economic implications of platelet glycoprotein IIb/IIIa blockade in patients undergoing coronary stenting: results from a multicentre randomised trial. EPISTENT Investigators. Evaluation of Platelet IIb/IIIa Inhibitor for Stenting. Lancet 1999;354:2019−2024. [Erratum in Lancet 2000;355:1104]. [PubMed]
80. The EPIC Investigation. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. N Engl J Med 1994;330:956−961. [PubMed]
81. Parving HH, Lehnert H, Brochner-Mortensen J, et al. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001;345:870−878. [PubMed]
82. Niskanen L, Hedner T, Hansson L, et al. Reduced cardiovascular morbidity and mortality in hypertensive diabetic patients on first-line therapy with an ACE inhibitor compared with diuretic/beta-blocker-based treatment regiment, a subanalysis of the Captopril Prevention Project. Diabetes Care 2001;24:2091−2096. [PubMed]
83. Tatti P, Pahor M, Byington RP, et al. Outcome results of the Fosinopril versus Amlodipine Cardiovascular Events randomised Trial (FACET) in patients with hypertension and NIDDM. Diabetes Care 1998;21:597−603. [PubMed]
84. Estacio RO, Jeffers BW, Hiatt WR, et al. The effect of nisoldipine as compared with enalapril on cardiovascular events in patients with non-insulin-dependent diabetes and hypertension. N Engl J Med 1998;338:645−652. [PubMed]
85. Lindholm LH, Hansson L, Ekbom T, et al. Comparison of antihypertensive treatment in preventing cardiovascular events in elderly diabetic patients: results from the Swedish trial in old patients with hypertension − 2. J Hypertens 2000;18:1671−1675. [PubMed]
86. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288:2981−2997. [PubMed]
87. Hansson L, Hedner T, Lund-Johansen P, et al. Randomized trial of effects of calcium antagonists compared with diuretics and beta-blockers on cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazem (NORDIL) study. Lancet 2000;356:359−365. [PubMed]
88. ALLHAT Collaborative Research Group. Major cardiovascular events in hypertensive patients randomised to doxazosin vs chlorthalidone: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). JAMA 2000;283:1967−1975. [PubMed]
2006; 2006: 0601.
Published online 2006 February 1.

Promoting smoking cessation

Summary

We found no direct information about promoting smoking cessation specifically in people with diabetes. Observational evidence and extrapolation from people without diabetes suggest that promotion of smoking cessation is likely to reduce cardiovascular events.

Benefits

We found no systematic review or RCTs on promotion of smoking cessation specifically in people with diabetes.

Harms

We found no RCTs.

Comment

Observational studies have found that cigarette smoking is associated with increased cardiovascular death in people with diabetes. Smoking cessation in people without diabetes has been found to be associated with reduced risk. People with diabetes are likely to benefit from smoking cessation at least as much as people who do not have diabetes but have other risk factors for cardiovascular events (see smoking cessation under secondary prevention of ischaemic cardiac events).

Substantive changes

No new evidence

2006; 2006: 0601.
Published online 2006 February 1.

Antihypertensive treatment versus no antihypertensive treatment

Summary

MORTALITY Compared with control: Blood pressure lowering with antihypertensive agents (angiotensin converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, calcium channel blockers, or diuretics) is more effective at reducing mortality in people with diabetes and hypertension or previous cardiovascular disease ( moderate-quality evidence ). CARDIOVASCULAR EVENTS Compared with control: Blood pressure lowering with antihypertensive agents (angiotensin converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, calcium channel blockers, or diuretics) is no more effective at reducing the incidence of myocardial infarction, stroke, or non-fatal cardiovascular events in people with diabetes and hypertension or previous cardiovascular disease ( high-quality evidence ).

Benefits

Antihypertensives versus control:

We found four systematic reviews (search date 2000, search date 2002, search date 2002, search date not reported ) and one meta-analysis of major RCTs. We also found three subsequent RCTs. Results are tabulated (see table 2) . All reviews and RCTs that analysed all cause mortality found that antihypertensives significantly reduced mortality in adults with diabetes with or without cardiovascular disease compared with control, and one large RCT found that antihypertensives reduced the incidence of stroke. One review analysed people with congestive heart failure with and without diabetes and found that the mortality risk reduction was not as great in people with diabetes as it was in the non-diabetic participants in the same trials (RR for non-diabetic participants: 0.72; 95% CI 0.65 to 0.79). None of the reviews or RCTs found that antihypertensives reduced myocardial infarction, cardiovascular mortality, or non-fatal cardiovascular events.

Table 2
Antihypertensives versus no antihypertensive treatment.

Harms

The systematic reviews and subsequent RCTs gave little information on adverse effects (see table 2 ).

Comment

None.

Substantive changes

No new evidence

2006; 2006: 0601.
Published online 2006 February 1.

Different antihypertensive drugs

Summary

CARDIOVASCULAR EVENTS ACE inhibitors compared with beta-blockers: Captopril and atenolol are equally effective at reducing cardiovascular events in people with type 2 diabetes and hypertension without a diagnosis of cardiovascular disease ( moderate-quality evidence ). ACE inhibitors compared with betablockers plus diuretics: Captopril may be more effective at reducing a combined outcome of acute myocardial infarction, stroke or death in people with type 2 diabetes and hypertension without a diagnosis of cardiovascular disease ( low-quality evidence ). ACE inhibitors compared with calcium channel blockers: Fosinopril, enalapril are more effective than amlodipine, nisoldipine at reducing myocardial infarction but are equally effective at reducing stroke in people with type 2 diabetes without cardiovascular disease (moderate-quality evidence). ACE inhibitors compared with diuretics: Lisinopril is less effective at reducing stroke or heart failure compared with chlorthalidone in people with type 2 diabetes and established hypertension (moderate-quality evidence). Calcium channel blockers compared with beta-blockers/ diuretics: Calcium channel blockers and beta-blockers/ diuretics are equally effective at reducing stroke but calcium channel blockers are less effective at reducing heart failure in people with diabetes and hypertension (moderate-quality evidence). Calcium channel blockers compared with ACE inhibitors/or angiotension II receptor antagonists: Amlodipine, nisolidpine, isradipine, felodipine and fosinopril, enalapril, lisinopril, irbesartan are equally effective at reducing myocardial infarction and stroke, but calcium channel blockers are less effective at reducing heart failure in people with diabetes (moderate-quality evidence). Angiotensin II receptor antagonists compared with beta-blockers: Losartan may be more effective than atenolol at reducing composite cardiovascular outcomes (mortality, stroke, and myocardial infarction) in people with type 2 diabetes with or without cardiovascular disease (low-quality evidence). Angiotensin II receptor antagonists compared with calcium channel blockers: Irbesartan is more effective than amlodipine at reducing heart failure but is equally effective at reducing myocardial infarction, and stroke in people with type 2 diabetes with hypertension or overt nephropathy, without a diagnosis of cardiovascular disease (moderate-quality evidence). MORTALITY ACE inhibitors compared with calcium channel blockers: Fosinopril, enalapril, and amlodipine, nisoldipine are equally effective at reducing mortality in people with type 2 diabetes without cardiovascular disease (moderate-quality evidence). ACE inhibitors compared with diuretics: Lisinopril and chlorthalidone are equally effective at reducing mortality in people with type 2 diabetes and established hypertension (low-quality evidence). Calcium channel blockers compared with beta-blockers/ diuretics: Calcium channel blockers and beta-blockers/ diuretics are equally effective at reducing mortality (moderate-quality evidence). Calcium channel blockers compared with ACE inhibitors/angiotensin II receptor antagonists: Amlodipine, nisolidpine, isradipine, felodipine and fosinopril, enalapril, lisinopril, irbesartan are equally effective at reducing mortality in people with diabetes (moderate-quality evidence). Angiotensin II receptor antagonists compared with calcium channel blockers: Irbesartan and amlodipine are equally effective at reducing mortality in people with type 2 diabetes with hypertension or overt nephropathy, without a diagnosis of cardiovascular disease (moderate-quality evidence).

Benefits

We found three systematic reviews, one additional RCT, and three subsequent RCTs comparing different antihypertensive drugs (angiotensin converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, beta-blockers, calcium channel blockers) versus each other in older people with diabetes, primarily type 2, with or without a diagnosis of cardiovascular disease. The first systematic review (search date 2002) assessed any type of antihypertensive agents and did not attempt to pool the results of the RCTs identified. The second review (search date 2000) compared ACE inhibitors versus other antihypertensive agents, and the third review (search date 2003) assessed calcium channel blockers. The second and third reviews pooled some of the same RCTs but combined data differently. We report the results of the relevant RCTs for each comparison identified by the reviews, reporting meta-analyses where possible. We also report the results of the subsequent RCTs. Most RCTs found no significant difference in mortality or cardiovascular events between different antihypertensive drugs. One RCT found that the ACE inhibitor lisinopril significantly increased stroke compared with the diuretic chlorthalidone. Two reviews suggested that calcium channel blockers offered significantly less protection against heart failure than did ACE inhibitors, angiotensin II receptor antagonists, beta-blockers, or diuretics. One RCT found that losartan significantly reduced composite cardiovascular outcomes compared with atenolol. Another RCT found that doxazosin significantly increased combined coronary events over 6 years compared with chlorthalidone and terminated treatment with doxazosin as a result (see table 3 ).

Table 3
Different antihypertensives versus each other.

Harms

Most of the RCTs gave no information on adverse effects. One RCT identified by the second systematic review found that people taking atenolol gained significantly more weight over the first 4 years of the trial than did those taking captopril. However, it found no significant difference between groups over the subsequent 4 years. One RCT found that people with and without diabetes taking verapamil had higher rates of constipation and cough than people taking atenolol, whereas people taking atenolol had higher rates of dyspnoea, light headedness, symptomatic bradycardia, and wheezing. RCTs found that people taking diltiazem had a significantly higher frequency of headaches and constipation than people taking diuretics or beta-blockers. One RCT found that discontinuation of treatment because of adverse effects was significantly more common with atenolol than with losartan. For full details see table B on web extra.

Comment

Clinical guide:

The evidence suggests that thiazide-like diuretics, beta-blockers, ACE inhibitors, and calcium channel blockers all reduce cardiovascular events in people with diabetes. The results of the review of calcium channel blockers cast doubt on the conclusions of earlier, smaller studies suggesting that ACE inhibitors are superior to calcium channel blockers. The review indicates that a calcium channel blocker is at least as effective as an ACE inhibitor as initial treatment for hypertension, in terms of prevention of major cardiovascular events. It is unclear whether ACE inhibitors and beta-blockers are equivalent. In most RCTs, combination treatment with more than one agent was required to achieve target blood pressures. One large RCT identified by a systematic review found that the ACE inhibitor ramipril, which reduces urinary protein excretion, also reduced cardiovascular morbidity and mortality in older diabetic people with other cardiac risk factors. The relative cardioprotective effect of the ACE inhibitor was present to the same extent in people with or without hypertension, and with or without microalbuminuria.

Substantive changes

No new evidence

2006; 2006: 0601.
Published online 2006 February 1.

Lower target blood pressure

Summary

CARDIOVASCULAR EVENTS Compared with moderate target blood pressures: Tighter control of blood pressure to a target diastolic blood pressure of 80 mm Hg or lower is more effective at reducing the risk of major cardiovascular events in people with type 2 diabetes ( moderate-quality evidence ). MORTALITY Intensive blood pressure lowering compared with normal baseline blood pressure: We don't know whether reducing the baseline target diastolic blood pressure below 10 mm Hg in normotensive people with diabetes is more effective at reducing all-cause mortality ( low-quality evidence ).

Benefits

We found no systematic review but found three RCTs. The first RCT (reported in two papers) found that, compared with a moderate target blood pressure (≤ 180/105 mm Hg), a tight target blood pressure (≤ 150/85 mm Hg) in people with type 2 diabetes significantly reduced fatal or non-fatal acute myocardial infarction and stroke but found no significant difference for peripheral vascular events over 8.4 years (1148 people with hypertension managed with atenolol or captopril; fatal or non-fatal acute myocardial infarction: 107/758 [14%] with tight blood pressure target v 83/390 [21%] with moderate blood pressure target; RR 0.66, 95% CI 0.51 to 0.86; NNT 14, 95% CI 9 to 35; stroke: 38/758 [5.0%] with tight blood pressure target v 34/390 [8.7%] with moderate blood pressure target; RR 0.58, 95% CI 0.37 to 0.90; NNT 27, 95% CI 18 to 116; peripheral vascular events: 8/758 [1.1%] with tight blood pressure target v 8/390 [2.1%] with moderate blood pressure target; RR 0.52, 95% CI 0.20 to 1.36). The second RCT found that the risk of major cardiovascular events was reduced by 50% over 3.8 years with a target diastolic blood pressure of 80 mm Hg or lower compared with a target blood pressure of 90 mm Hg or lower (1 multicentre RCT, 3 arm study, 1501 people with hypertension managed with felodipine, ACE inhibitors, beta-blockers, or diuretics; major cardiovascular events: 22/499 [4.4%] with target blood pressure ≤ 80 mm Hg v 45/501 [9.0%] with target blood pressure ≤ 90 mm Hg; RR 0.5, 95% CI 0.3 to 0.8; NNT 22, 95% CI 16 to 57). The third RCT found a significantly lower incidence of cerebrovascular accidents with a target diastolic blood pressure of 10 mm Hg below baseline using nisoldipine or enalapril compared with an unchanged baseline diastolic blood pressure of 80−89 mm Hg with placebo over 5.3 years (480 people with type 2 diabetes and baseline blood pressure < 140/90 mm Hg being managed with nisoldipine or enalapril; cerebrovascular accidents: 4/237 [1.7%] with a target diastolic blood pressure of 10 mm Hg below baseline v 13/243 [5.4%] with an unchanged baseline diastolic blood pressure of 80−89 mm Hg; OR 3.29, CI 1.06 to 10.25; NNT 27, 95% CI 14 to 255). The RCT found no significant difference in cardiovascular death, myocardial infarction, congestive heart failure, or all cause mortality. The RCT also found that, in a subgroup of people with type 2 diabetes and peripheral arterial disease at baseline (ankle : brachial index < 0.90), intensive blood pressure lowering to a mean of 128/75 mm Hg compared with no blood pressure reduction significantly reduced major cardiovascular events (53 people, cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, heart failure requiring hospital admission, or pulmonary infarction: 3/22 [13.6%] with intensive blood pressure lowering v 12/31 [38.7%] with no blood pressure reduction; ARR 25%, 95% CI 3% to 47%; NNT 4, 95% CI 2 to 37).

Harms

We found no good evidence of a threshold below which it is harmful to lower blood pressure. One RCT found that a significantly greater proportion of people gained weight with atenolol than with captopril (mean weight gain over 9 years: 3.4 kg with atenolol v 1.6 kg with captopril; P = 0.02) but it found no significant difference in hypoglycaemia or weight gain with tight blood pressure control (≤ 150/85 mm Hg) compared with moderate blood pressure control (≤ 180/105 mm Hg). The second RCT comparing tight versus moderate blood pressure control reported adverse effects including dizziness, headache, leg oedema, flushing, and coughing. The study suggested an increased risk of cardiovascular death at the lowest achieved blood pressure, and aspirin was associated with a higher overall rate of major and minor bleeds (about 1.8 times higher). The third RCT in normotensive people gave no information on adverse effects.

Comment

Aggressive lowering of blood pressure in people with diabetes and hypertension reduces cardiovascular morbidity and mortality. In most trials, combination treatment with more than one agent was required to achieve target blood pressures.

Substantive changes

No new evidence

2006; 2006: 0601.
Published online 2006 February 1.

Fibrates

Summary

CARDIOVASCULAR EVENTS Compared with placebo: Gemfibrozil, and bezafibrate may be more effective at reducing coronary heart disease, death, stroke or non-fatal acute myocardial infarction at 5 years in people with diabetes and cardiovascular disease ( low-quality evidence ). MORTALITY Compared with placebo: We don't know whether fibrates are more effective at reducing mortality in people with diabetes and cardiovascular disease (low-quality evidence).

Benefits

We found two systematic reviews (search date not reported, search date 2002) comparing fibrates with placebo. Neither of these systematic reviews included pooling or summary estimates across the fibrate trials. We have reported the results of individual RCTs identified by at least one of the systematic reviews. One RCT found that gemfibrozil did not significantly reduce myocardial infarction or cardiac death over 5 years compared with placebo (135 men aged 40−55 years with diabetes without a diagnosis of cardiovascular disease, with non-high density lipoprotein (HDL) cholesterol > 5.2 mM; 200 mg/dL: 2/59 [3.4%] events with gemfibrozil v 8/76 [10.5%] with placebo; ARR 7%, 95% CI – 1% to + 15%; RR 32%, 95% CI 7% to 146%). The study reported greater changes from baseline serum lipid levels with gemfibrozil compared with placebo in men with diabetes (gemfibrozil results presented graphically; significance assessment not performed). A second RCT found that, compared with placebo, gemfibrozil 1200 mg daily significantly reduced coronary heart disease, death, stroke, or non-fatal acute myocardial infarction over 5 years (769 men aged < 74 years with diabetes and cardiovascular disease diagnosis, with high density lipoprotein cholesterol ≤ 40mg/dL, low density lipoprotein cholesterol ≤ 140mg/dL, and tricgylceride ≤ 300 mg/dL: 105/388 [27%] events with gemfibrozil v 141/381 [37%] events with placebo; HR 0.68, 95% CI 0.53 to 0.88). A third RCT found that bezafibrate significantly reduced myocardial infarction or new ischaemic changes on electrocardiogram over 3 years compared with placebo (164 people aged 35−65 years with type 2 diabetes without a diagnosis of cardiovascular disease, with serum triglyceride 8.18–8.0 mmol/L, serum cholesterol 5.2–8.0 mmol/L, and total to HDL cholesterol ratio between ≥ 4.7 to ≥ 7.2; 5/64 [7.8%] events with bezafibrate v 16/64 [25%] events with placebo; ARR 17.2%, 95% CI 4.6% to 30.1%; RR 0.31, 95% CI 0.12 to 0.80; NNT 6, 95% CI 5 to 20). It also found that bezafibrate significantly improved serum lipid levels at 3 years (total cholesterol median change from baseline [range: 5.60–5.77 mmol/L]: –4.8 with bezafibrate v + 0.20 with placebo; P = 0.004; triglyceride median change from baseline [range: 2.09–2.24 mmol/L]: – 0.80 with bezafibrate v –0.09 with placebo; P = 0.001; HDL cholesterol median change from baseline [range: 0.94–1.02 mmol/L]: + 0.02 with bezafibrate v –0.02 with placebo; P = 0.001). The reduction in median low density lipoprotein cholesterol did not reach significance (low density lipoprotein cholesterol median change from baseline [range: 3.66–3.98]: –0.35 with bezafibrate v –0.04 with placebo; P = 0.06). A fourth RCT found no significant difference in the proportion of people who either had myocardial infarction or died after 39 months of treatment between fenofibrate 200 mg daily and placebo (418 people with diabetes and with or without cardiovascular disease diagnosis, mean age 57 years: 15/207 [7.2%] events with fenofibrate v 21/211 [9.9%] events with placebo; ARR + 2.7%, 95% CI −2.8% to + 8.3%; RR 0.73, 95% CI 0.39 to 1.37). It found that, compared with placebo, fenofibrate significantly improved serum lipid levels from baseline (total plasma cholesterol reduction from baseline [range: 5.56–5.58]: data presented graphically; P < 0.001); low density lipoprotein cholesterol reduction from baseline [range: 3.38–3.43]: data presented graphically; P < 0.001; triglyceride reduction from baseline [range: 2.42–2.59]: data presented graphically; P < 0.001; HDL cholesterol increase from baseline [range: 1.01–1.05]: data presented graphically; P < 0.001). This RCT was underpowered for the outcomes of myocardial infarction and death, but there were trends toward reduced risk of myocardial infarction with fenofibrate (9 with fenofibrate v 12 with placebo) and death (6 with fenofibrate v 9 with placebo). A benefit for fenofibrate in reducing myocardial infarction and death is suggested and certainly cannot be excluded.

Harms

The systematic reviews did not comment on adverse effects. The first, second, and third RCT did not comment on adverse effects. The RCT comparing fenofibrate 200 mg daily and placebo reported no significant difference between fenofibrate and placebo in gallbladder symptoms (1/207 [0.5%] with fenofibrate v 3/211 [1.4%] with placebo), liver toxicity (3/207 [1.5%] with fenofibrate v 0/211 [0%] with placebo), muscle pain (0/207 [0%] with fenofibrate v 1/211 [0.5%] with placebo), joint pain (7/207 [3.4%] with fenofibrate v 6/211 [2.5%] with placebo), or cancer (5/207 [2.4%] with fenofibrate v 7/211 [3.3%] with placebo).

Comment

None.

Substantive changes

No new evidence

2006; 2006: 0601.
Published online 2006 February 1.

Statins versus placebo

Summary

CARDIOVASCULAR EVENTS Compared with placebo: Statins are more effective at reducing cardiovascular events in people with type 2 diabetes ( low-quality evidence ).

Benefits

We found one systematic review, two additional RCTs, and one subsequent RCT. We also found a systematic review that did not conduct a meta-analysis for RCTs evaluating statins, but provided a commentary on the quality of data on people with diabetes included in such trials (see comment below).

Statins versus placebo:

We found one systematic review (search date 2002), which pooled data from RCTs comparing statins or fibrates with placebo. We also found one subsequent RCT. The review found that that statins and fibrates were significantly more effective in primary prevention of cardiovascular events including non-fatal acute myocardial infarction, stroke, cardiovascular mortality, and unstable angina compared with placebo (6 RCTs, 5 with statins,1 with fibrates; 7200 people with type 2 diabetes; cardiovascular events: 352/3598 [9.8%] with statins or fibrates v 455/3602 [12.6%] with placebo; RR 0.78, 95% CI 0.67 to 0.89; ARR 3%, 95% CI 1% to 4% in 4.3 years; NNT 35, 95% CI not reported). It also found that statins and fibrates were significantly more effective in secondary prevention of cardiovascular events (8 RCTs, 7 with statins, 1 with fibrate; 4723 people with type 2 diabetes and coronary artery disease; cardiovascular events: 667/2359 [28%] with statin or fibrate v 817/2364 [34.6%] with placebo; RR 0.76, 95% CI 0.5 to 0.93; ARR 7%, 95% CI 3% to 12% in 4.9 years; NNT 13.8, 95% CI not reported). Sensitivity analyses excluding the fibrate trials did not alter the estimated relative risk or absolute risk reduction for primary or secondary prevention. The subsequent RCT (2838 people with type 2 diabetes, mean age 61 years, no prior history of cardiovascular disease, with at least one of hypertension, current smoking, albuminuria, or retinopathy; with low density lipoprotein (LDL) cholesterol < 4.1 mmol/L, followed for 3.9 years) found that atorvastatin significantly reduced cardiovascular events compared with placebo (cardiovascular events: 83/1428 [5.8%] with atorvastatin v 127/1410 [9%] with placebo; RR 0.63, 95% CI 0.48 to 0.83, P = 0.001).

Harms

Statins versus placebo:

The systematic review (search date 2002) reported similar levels of discontinuation for statins and placebo (reported as > 15% in many cases), and no significant difference in rates of elevated liver muscles enzymes in the larger scale studies (1 RCT, 3983 people with type 2 diabetes; rates of alanine aminotransferase > twice normal upper limit: 1.8% with simvastatin v 1.6% with placebo; reported as non-significant; rates of elevated creatine kinase: 0.3% with simvastatin v 0.2% with placebo; reported as non-significant).

Drug safety alert

MHRA issues drug safety alert on haemorrhagic stroke associated with high doses of atorvastatin in people with recent haemorrhagic stroke (3 December 2007).

Since the last update of this review, a drug safety alert has been issued on the increased risk of haemorrhagic stroke associated with high doses of atorvastatin in people with recent haemorrhagic stroke (http://www.mhra.gov.uk).

Comment

One RCT included in the systematic review is of major importance. The RCT is interesting because it was not necessary to have an abnormal lipid profile or prior vascular disease to be enrolled, and it provides the first clear evidence that statin treatment is effective for primary prevention of cardiovascular disease. The relative risk reductions for major cardiovascular events were similar with or without previous coronary heart disease, and with lower and higher initial LDL cholesterol. The results of this RCT suggest that treatment with a statin is likely to be beneficial in most diabetic people who are at significant risk of coronary heart disease, regardless of initial LDL level and regardless of whether they have had previous cardiovascular disease. Furthermore, this and other studies provided stronger evidence for the value of treatment with statins per se, rather than for targeting any specific LDL cholesterol level. Besides this RCT, most published RCTs with sufficient power to detect effects on cardiovascular events have enrolled comparatively few people with diabetes or have excluded them altogether. The available evidence is, therefore, based almost entirely on subgroup analyses of larger trials, in which there was generally little information regarding the type and duration of diabetes, severity of complications, and metabolic control. The statin versus placebo trial published after both systematic reviews was terminated early due to the high efficacy of atorvastatin in the overall study population (HR for cardiovascular death plus non-fatal myocardial infarction 0.64, 95% CI 0.50 to 0.83). Although the difference was not significant in the diabetic subgroup, the confidence intervals for diabetic and non-diabetic subgroups overlapped one another. Several large ongoing trials are evaluating the effects of fibrates in people with diabetes.

Substantive changes

No new evidence

2006; 2006: 0601.
Published online 2006 February 1.

Aggressive versus moderate lipid lowering with statins

Summary

CARDIOVASCULAR EVENTS Aggressive compared with moderate lipid lowering: We don't know whether aggressive lipid lowering is more effective at reducing myocardial infarction, congestive heart failure, revascularisation, and stroke at 3–4 years in people with type 2 diabetes and cardiovascular disease ( low-quality evidence ). MORTALITY Aggressive compared with moderate lipid lowering: We don't know whether aggressive lipid lowering is more effective at reducing mortality at 3–4 years in people with type 2 diabetes and cardiovascular disease (low-quality evidence).

Benefits

We found one systematic review, two additional RCTs, and one subsequent RCT. We also found a systematic review that did not conduct a meta-analysis for RCTs evaluating statins, but provided a commentary on the quality of data on people with diabetes included in such trials (see comment below).

Aggressive versus moderate lipid lowering:

One RCT included in the systematic review found no significant difference between aggressive lipid lowering and moderate lipid lowering in 4 year event rate for myocardial infarction and death (116 people aged 21–74 years with type 2 diabetes and a diagnosis of cardiovascular disease; 4 year event rate for death: 6.5 with aggressive lipid lowering v 9.6 with moderate lipid lowering; RR 0.67, 95% CI 0.12 to 3.75; 4 year event rate for myocardial infarction: 4.8 with aggressive lipid lowering v 11.6 with moderate lipid lowering; RR 0.40, 95% CI 0.07 to 2.47). The RCT used lovastatin and cholestyramine as necessary to achieve the targets for aggressive lipid lowering (LDL cholesterol 1.55–2.20 mmol/L [60–85 mg/dL]) and moderate lipid lowering (LDL cholesterol 3.36−3.62 mmol/L [130–140 mg/dL]). This RCT had limited power because of the small number of people enrolled who had diabetes. The first additional RCT found that, compared with usual care, treatment with atorvastatin to achieve a target LDL of below 2.6 mmol/L (< 100 mg/dL) significantly reduced the risk of all cause mortality, non-fatal myocardial infarction, unstable angina, congestive heart failure, revascularisation, and stroke over 3 years (313 people with a diagnosis of cardiovascular disease, mean age 58 years: RRR 0.42%; P = 0.0001; results presented graphically). The atorvastatin dose was titrated from 10 mg daily to a maximum of 80 mg daily to achieve a target LDL cholesterol of below 2.6 mmol/L. Usual care consisted of treatment by the family practitioner, which could include diet, exercise, weight loss, and/or drug treatment including lipid lowering agents; 14% of people in the usual care group received any lipid lowering agents.

Harms

Aggressive versus moderate lipid lowering:

The RCT included in the review did not report on adverse events. The additional RCT found no significant difference between atorvastatin and usual care in the proportion of people withdrawn from the study because of adverse effects (withdrawals because of adverse effects: 6/800 [0.75%] with atorvastatin v 3/800 [0.4%] with usual care; P reported as non-significant; withdrawals because of elevated liver enzymes: 4/800 [0.5%] with atorvastatin v 3/800 [0.4%] with usual care; significance not assessed).

Drug safety alert

MHRA issues drug safety alert on haemorrhagic stroke associated with high doses of atorvastatin in people with recent haemorrhagic stroke (3 December 2007).

Since the last update of this review, a drug safety alert has been issued on the increased risk of haemorrhagic stroke associated with high doses of atorvastatin in people with recent haemorrhagic stroke (http://www.mhra.gov.uk).

Comment

See comment about statins versus placebo.

Substantive changes

No new evidence

2006; 2006: 0601.
Published online 2006 February 1.

Low versus standard statin dose in older people

Summary

CARDIOOVASCULAR EVENTS Low dose pravastatin compared with standard doses: Low dose and standard doses of pravastatin are equally effective at 4 years at reducing cardiovascular events in diabetics over 60 years of age ( moderate-quality evidence ).

Benefits

We found one systematic review, two additional RCTs, and one subsequent RCT. We also found a systematic review that did not conduct a meta-analysis for RCTs evaluating statins, but provided a commentary on the quality of data on people with diabetes included in such trials (see comment below).

Low versus standard statin dose in older people:

The second additional RCT found no significant difference in cardiovascular events in older people between low dose pravastatin 5 mg daily and standard dose pravastatin 10−20 mg daily over 4 years (199 people aged > 60 years with diabetes: 17/104 [16.3%] events with low dose pravastatin v 15/95 [15.8%] events with standard dose pravastatin; ARR + 0.6%, 95% CI −9.7% to + 10.8%).

Harms

Low versus standard statin dose in older people:

In the additional RCT comparing low versus standard pravastatin dose, adverse effects included gastrointestinal symptoms and elevated creatine kinase and were higher in the standard dose group (proportion of adverse events: 19/334 [5.7%] with low dose pravastatin v 26/331 [7.9%] with standard dose pravastatin; P value not reported).

Comment

See comment about statins versus placebo.

Substantive changes

No new evidence

2006; 2006: 0601.
Published online 2006 February 1.

Aspirin

Summary

CARDIOVASCULAR EVENTS Compared with placebo/control: Aspirin is no more effective at reducing myocardial infarction, stroke, cardiovascular death in people with diabetes, and with or without a cardiovascular disease diagnosis ( moderate-quality evidence ). Compared with clopidogrel: Aspirin and clopidogrel are equally effective at 28 days at reducing cardiovascular events in people with type 1 and type 2 diabetes and with recent stroke, myocardial infarction, or established arterial disease ( high-quality evidence ). Compared with clopidogrel plus aspirin: Taking clopidogrel in addition to aspirin is no more effective at reducing cardiovascular events at 12 months in people with diabetes presenting with unstable angina or non-Q wave myocardial infarction, and increases the proportion of people who have major bleeds (high-quality evidence). MORTALITY Compared with placebo/control: Aspirin is no more effective at reducing the composite endpoint of non-fatal mycocaridal infarction, non-fatal stroke, death from a vascular cause, or death from an unknown cause in people with diabetes and with a cardiovascular disease diagnosis (moderate-quality evidence). ADVERSE EFFECTS Antiplatelets have been associated with an increase in the risk of major extracranial haemorrhage and haemorrhagic stroke.

Benefits

Aspirin versus placebo or control:

We found one systematic review (search date 1997), one additional RCT, and one subsequent RCT. The review found that, compared with controls, antiplatelet treatment mainly with aspirin did not significantly reduce the combined risk of non-fatal myocardial infarction, non-fatal stroke, death from a vascular cause, or death from an unknown cause (9 RCTs, 4961 people with unspecified diabetes and cardiovascular disease diagnosis; 403/2568 [15.7%] with antiplatelet treatment v 426/2558 [16.7%] with control; RR 0.94, 95% CI 0.83 to 1.07). This non-significant 6% relative risk reduction contrasted with a significant 25% relative risk reduction for the same outcomes in the full meta-analysis (people with or without diabetes combined). The largest RCT included in the systematic review found no significant difference in reduction of fatal or non-fatal myocardial infarction or stroke at 5 years between aspirin 650 mg daily compared with placebo (3711 people with type 1 and 2 diabetes aged 18−70 years; fatal or non-fatal myocardial infarction at 5 years: 9.1% with aspirin v 12.3% with placebo; RR 0.83, 99% CI 0.66 to 1.04; fatal or non-fatal stroke: 4.5% with aspirin v 3.8% with placebo; RR 1.17, 95% CI 0.79 to 1.28). The additional RCT found that aspirin significantly reduced the risk of acute myocardial infarction over 5 years compared with placebo (533 male physicians with diabetes but no diagnosis of cardiovascular disease: 11/275 [4.0%] with aspirin v 26/258 [10.1%] with placebo; RR 0.39, 95% CI 0.20 to 0.79; NNT 16, 95% CI 12 to 47). One subsequent open label RCT (1031 people, mean age 64 years with type 2 diabetes and no history of a major cardiovascular event) found that aspirin did not significantly reduce cardiovascular death, stroke, or myocardial infarction compared with no treatment (total cardiovascular events: 53/519 [10.2%] with aspirin v 59/512 [11.5%] with no treatment; RR 0.89% 95% CI 0.62% to 1.26%).

Aspirin versus clopidogrel:

See benefits of clopidogrel.

Aspirin plus clopidogrel:

See benefits of adding clopidogrel to aspirin in acute coronary syndromes.

Harms

In the systematic review, doses of aspirin ranged from 75−1500 mg daily. Most RCTs used aspirin 75−325 mg daily. Doses higher than 325 mg daily increased the risk of haemorrhagic adverse effects without improving preventive efficacy. No difference in efficacy or adverse effects was found in the dose range 75−325 mg daily. The systematic review found that antiplatelet treatment with aspirin was associated with a 50% relative increase in the odds of major extracranial haemorrhage (OR 1.6, 95% CI 1.4 to 1.8) and a relative increase in the risk of haemorrhagic stroke (RR 22%, 95% CI 3% to 44%, P < 0.01). These results were for the overall meta-analysis; results were not reported separately for the people with diabetes. The largest RCT in people with diabetes included in the systematic review did not report on harms. The additional RCT found that aspirin significantly increased the risk of bleeding compared with placebo (22 071 physicians, of which 533 had diabetes; proportion with bleeding: 2979/22 071 [13.5%] with aspirin v 2248/22 071 [10.1%] with placebo; RR 1.32; 95% CI 1.25 to 1.40; P < 0.00001). It found no significant differences for other frequent adverse effects. These results were for the overall analysis; results were not reported separately for the people with diabetes. The subsequent open label RCT found that aspirin significantly increased bleeding complications (1.9% with aspirin v 0.2% with no treatment; P = 0.007, absolute data not reported).

Comment

We found insufficient evidence to define precisely which people with diabetes should be treated with aspirin. The risk of cardiovascular disease is low before 30 years of age; most white adults with diabetes aged over 30 years are at increased risk of cardiovascular disease. Widely accepted contraindications to aspirin treatment include aspirin allergy, bleeding tendency, anticoagulant treatment, recent gastrointestinal bleeding, and clinically active liver disease.

Substantive changes

No new evidence

2006; 2006: 0601.
Published online 2006 February 1.

Clopidogrel

Summary

CARDIOVASCULAR EVENTS Compared with aspirin: Clopidogrel and aspirin are equally effective at 28 days at reducing cardiovascular events in people with type 1 and type 2 diabetes and with recent stroke, myocardial infarction, or established arterial disease ( high-quality evidence ). Compared with clopidogrel plus aspirin: Taking clopidogrel in addition to aspirin is no more effective at reducing cardiovascular events at 12 months in people with diabetes presenting with unstable angina or non-Q wave myocardial infarction, and increases the proportion of people who have major bleeds (high-quality evidence). NOTE We found no direct information about whether clopidogrel is better than no active treatment.

Benefits

We found no systematic reviews.

Clopidogrel versus placebo:

We found no RCTs comparing clopidogrel versus placebo.

Clopidogrel versus aspirin:

One RCT in people in people with type 1 and type 2 diabetes and with recent ischaemic stroke, acute myocardial infarction, or established peripheral arterial disease found no significant difference in cardiovascular events between clopidogrel and aspirin at 28 days (3866 people, mean age 64 years; angina, vascular death, myocardial infarction, all cause stroke, and readmission to hospital for ischaemic events: 299/1914 [15.6%] with clopidogrel v 345/1952 [17.7%] with aspirin; ARR 2.1%, 95% CI −0.3% to + 4.4%; RR 0.88, 95% CI 0.77 to 1.02).

Clopidogrel plus aspirin:

See benefits of adding clopidogrel to aspirin in acute coronary syndromes.

Harms

Clopidogrel versus placebo:

One RCT found that a significantly lower proportion of people with type 1 and type 2 diabetes were hospitalised for a bleeding event with clopidogrel than with aspirin at 28 days (3866 people, mean age 64 years; hospital admission for a bleeding event: 34/1914 [1.8%] with clopidogrel v 55/1952 [2.8%] with aspirin; RRR 37.0%, 95% CI 3.8% to 58.7%; P = 0.031).

Comment

None.

Substantive changes

No new evidence

2006; 2006: 0601.
Published online 2006 February 1.

Adding clopidogrel to aspirin in acute coronary syndromes

Summary

CARDIOVASCULAR EVENTS Clopidogrel plus aspirin compared with aspirin: Taking clopidogrel in addition to aspirin is no more effective at reducing cardiovascular events at 12 months in people with diabetes presenting with unstable angina or non-Q wave myocardial infarction, and increases the proportion of people who have major bleeds ( high-quality evidence ).

Benefits

Adding clopidogrel to aspirin:

One RCT in people presenting with unstable angina or non-Q wave myocardial infarction and also taking aspirin found no significant reduction in cardiovascular events after 12 months with added clopidogrel compared with added placebo (2840 people with unspecified diabetes, mean age 64 years; cardiovascular death, non-fatal myocardial infarction, or stroke at 12 months: 200/1405 [14.2%] with clopidogrel v 240/1435 [16.7%] with placebo; RR 0.85, 95% CI 0.71 to 1.01). People were randomised within 24 hours of an acute event and were given either clopidogrel 300 mg bolus and then 75 mg daily plus aspirin 75−325 mg daily or placebo plus aspirin.

Harms

Adding clopidogrel to aspirin:

One RCT in people presenting with unstable angina or non-Q wave myocardial infarction and also taking aspirin found a significantly higher proportion of major bleeds with clopidogrel than with placebo (major bleeds: 3.7% with clopidogrel v 2.7% with placebo; RR 1.38, 95% CI 1.13 to 1.67; P = 0.001).

Comment

None.

Substantive changes

No new evidence

2006; 2006: 0601.
Published online 2006 February 1.

Glycoprotein IIb/IIIa inhibitors

Summary

CARDIOVASCULAR EVENTS Glycoprotein IIb/IIIa inhibitors plus heparin compared with heparin alone: Adding tirofiban (a glycoprotein IIb/IIIa inhibitor) to heparin is more effective at reducing a composite outcome of death, myocardial infarction, or refractory ischaemia at 180 days in people presenting with unstable angina or acute myocardial infarction without ST segment elevation and who are taking aspirin ( moderate-quality evidence ). Glycoprotein IIb/IIIa inhibitors plus fibrinolytics compared with fibrinolytics alone: Abciximab plus half dose reteplase is more effective than full dose reteplase at 7 days at reducing a composite outcome of death, recurrent myocardial infarction, recurrent angina, ischaemia, and revascularisation in people with type 1 and 2 diabetes presenting with acute ST segment elevation myocardial infarction but increases the risk of bleeding (moderate-quality evidence). NOTE We found no clinically important results about glycoprotein IIb/IIIa inhibitors compared with no antiplatelet treatment in prevention of cardiovascular events in people with diabetes. RCTs in people undergoing percutaneous transluminal coronary angioplasty found that the combination of glycoprotein IIb/IIIa inhibitor plus stent reduced cardiovascular morbidity and mortality compared with placebo plus stent.

Benefits

We found no systematic reviews.

Glycoprotein IIb/IIIa inhibitors versus no antiplatelet treatment:

We found no RCTs comparing glycoprotein IIb/IIIa inhibitors versus no antiplatelet treatment.

Adding glycoprotein IIb/IIIa inhibitors to heparin:

One RCT, in people with type 1 and type 2 diabetes presenting with unstable angina or acute myocardial infarction without ST segment elevation, found that adding tirofiban (a glycoprotein IIb/IIIa inhibitor) to heparin compared with heparin alone significantly reduced the composite outcome of death, myocardial infarction, or refractory ischaemia at 180 days (362 people already taking aspirin, mean age 65 years: 19/169 [11.2%] with tirofiban plus heparin v 37/193 [19.2%] with heparin alone; ARR 8.0%, 95% CI 0.7% to 15.3%; RR 59%, 95% CI 35% to 98%; P = 0.03; NNT 13, 95% CI 7 to 146).

Glycoprotein IIb/IIIa inhibitors as an adjunct to percutaneous coronary revascularisation:

See benefits of intracoronary stenting plus glycoprotein IIb/IIIa inhibitors.

Adding glycoprotein IIb/IIIa inhibitors to fibrinolytic therapy:

One RCT in people presenting with acute ST segment elevation myocardial infarction found that combination of abciximab plus half dose reteplase significantly reduced recurrent myocardial infarction compared with full dose reteplase alone at 7 days (2633 people with type 1 and type 2 diabetes, mean age 64 years: rate of recurrent myocardial infarction at 7 days: 33/1334 [2.5%] with abciximab plus reteplase v 56/1299 [4.3%] with retiplase alone; ARR 1.8%, 95% CI 0.4% to 3.2%; NNT 54, 95% CI 31 to 221). Abciximab plus half dose reteplase also significantly reduced the composite outcome of death, recurrent myocardial infarction, recurrent angina, ischaemia, and revascularisation compared with full dose reteplase alone at 7 days (540/1334 [40.5%] with abciximab plus reteplase v 584/1299 [45%] with retiplase alone; P = 0.021; ARR 4.5%, 95% CI 0.7% to 8.3%; NNT 22, 95% CI 12 to 142).

Harms

Adding glycoprotein IIb/IIIa inhibitors to heparin:

One RCT found no significant difference between tirofiban plus heparin and heparin alone in the risk of bleeding in people already taking aspirin (9.5% with tirofiban plus heparin v 8.3% with heparin alone; RR 1.16, 95% CI 0.56 to 2.39).

Adding glycoprotein IIb/IIIa inhibitors to fibrinolytic therapy:

The RCT in people presenting with acute ST segment elevation myocardial infarction found a significant increase in bleeding with abciximab plus half dose reteplase compared with reteplase alone (rate of bleeding: 356/1334 [26.7%] with abciximab plus reteplase v 184/1299 [14.2%] with reteplase alone; P < 0.001).

Comment

None.

Substantive changes

No new evidence

2006; 2006: 0601.
Published online 2006 February 1.

Intensive blood glucose control

Summary

CARDIOVASCULAR EVENTS Intensive compared with conventional glycaemic control in type 1 diabetes: Intensive glycaemic control for more than 2 years is more effective at reducing the occurrence of a first major cardiovascular event in people with type 1 diabetes ( high-quality evidence ). Intensive compared with conventional glycaemic control in type 2 diabetes (without a diagnosis of cardiovascular disease): Intensive glycaemic control and conventional glycaemic control are equally effective at reducing the occurrence of a myocardial infarction, or stroke at 5 years in people with type 2 diabetes and no diagnosis of cardiovascular disease (high-quality evidence). Intensive compared with conventional glycaemic control in type 2 diabetes (with previous cardiovascular events): We don't know whether an intensive insulin treatment with a stepped plan to achieve near normal blood sugar levels is more effective than standard once daily insulin injection at preventing the occurence of new cardiovascular events in people with type 2 diabetes and previous cardiovascular events ( low-quality evidence ). NOTE Intensive glycaemic control is more likely to cause weight gain and hypoglycaemic episodes compared with conventional treatment.

Benefits

We found one systematic review (search date 1996) and two subsequent RCTs.

Intensive versus conventional glycaemic control in type 1 diabetes:

The systematic review found that, compared with conventional glycaemic control, intensive glycaemic control for more than 2 years significantly reduced the occurrence of a first major cardiovascular event in people with type 1 diabetes (6 RCTs, 1731 people aged 30−42 years with type 1 diabetes; number of first major cardiovascular events: 27/961 [2.8%] with intensive control v 55/970 [5.7%] with conventional glycaemic control; OR 0.55, 95% CI 0.35 to 0.88). Major macrovascular events were defined as fatal or non-fatal myocardial infarction, sudden cardiac death, revascularisation procedure, angina with confirmed coronary artery disease, stroke, lower limb amputation, peripheral arterial events, and peripheral vascular disease. Conventional glycaemic control consisted of one or two daily injections of insulin without self adjustment of insulin dosage according to blood or urine glucose monitoring results. Intensive glycaemic control consisted of three or more injections of insulin with the dosage adjusted according to self monitoring of blood glucose levels.

Intensive versus conventional glycaemic control in type 2 diabetes:

The first subsequent in people with type 2 diabetes found no significant difference between intensive and conventional glycaemic control in myocardial infarction or stroke over 5 years (1138 people with type 2 diabetes but without a diagnosis of cardiovascular disease, mean age 54 years; myocardial infarction: 387/2729 [14.2%] with intensive control v 186/1138 [16.3%] with conventional control; RR 0.84, 95% CI 0.71 to 1.00; P = 0.052; stroke: 148/2729 [5.4%] with intensive control v 55/1138 [4.8%] with conventional control; RR 1.11, 95% CI 0.81 to 1.51). The second subsequent RCT in people with type 2 diabetes found no significant difference between intensive insulin treatment with a stepped plan designed to achieve near normal blood sugar levels and standard once daily insulin injection in the rate of new cardiovascular events over 27 months (153 men with type 2 diabetes, mean age 60 years, many of whom had previous cardiovascular events; new cardiovascular events: 24/75 [32%] with intensive treatment v 16/80 [20%] with standard treatment; RR 1.60, 95% CI 0.92 to 2.50).

Harms

Intensive versus conventional glycaemic control in type 1 diabetes:

The systematic review did not comment on harms. The largest RCT included in the review found that weight gain and waist to hip ratio were significantly increased in the intensive treatment group compared with conventional treatment (weight gain: P ≤ 0.001; waist to hip ratio: P = 0.02).

Intensive versus conventional glycaemic control in type 2 diabetes:

The first subsequent RCT found that intensive treatment significantly increased weight gain and hypoglycaemic episodes compared with conventional treatment (weight gain: data presented graphically; P < 0.0001; hypoglycaemic episodes: data presented graphically; P < 0.0001). The second subsequent RCT found significantly higher mild and moderate hypoglycaemic events with intensive treatment compared with conventional treatment (proportion of hypoglycaemic events per patient per year: 16.5 with intensive treatment v 1.5 with conventional treatment; P < 0.01). However, it was noted that some hypoglycaemic episodes may not have been detected in the conventional treatment group because of less frequent measurement of blood glucose levels.

Comment

The role of intensive glucose lowering in primary prevention of cardiovascular events remains unclear. However, such treatment clearly reduces the risk of microvascular disease and does not increase the risk of cardiovascular disease. The potential of the largest RCT in people with type 2 diabetes to show an effect of tighter glycaemic control was limited by the small difference achieved in median HbA1c between intensive and conventional treatment and the relatively low risk of cardiovascular disease. By contrast, in another primary prevention trial, a larger difference (1.9%) in median HbA1c was achieved between groups (mean HbA1c levels: 7.2% with intensive treatment v 9.1% with conventional treatment; P < 0.001), but the young age of the participants and consequent low incidence of cardiovascular events limited the power of the study to detect an effect of treatment on the incidence of cardiovascular disease. The RCT of insulin in type 2 diabetes included men with a high baseline risk of cardiovascular events and achieved a 2.1% absolute difference in HbA1c (mean HbA1c levels at 6 months: 7.1% with intensive treatment v 9.2% with conventional treatment; P < 0.001). The RCT was small and the observed difference between groups could have arisen by chance.

Substantive changes

No new evidence

2006; 2006: 0601.
Published online 2006 February 1.

Metformin versus diet alone as initial treatment in overweight or obese people with type 2 diabetes

Summary

CARDIOVASCULAR EVENTS Metformin compared with diet: Intensive treatment with metformin is more effective than conventional treatment with diet alone at reducing the incidence of myocardial infarction but not stroke at 5 years in overweight or obese people with type 2 diabetes without a diagnosis of cardiovascular disease ( high-quality evidence ).

Benefits

Metformin versus diet alone in overweight or obese people with type 2 diabetes:

We found one RCT in overweight or obese people with type 2 diabetes, which found that intensive treatment with metformin compared with conventional treatment with diet alone reduced myocardial infarction and stroke over 5 years, but this reduction did not reach significance for stroke (753 people without a diagnosis of cardiovascular disease, mean age 53 years; myocardial infarction: 39/342 [11%] with metformin v 73/411 [18%] with diet alone; RR 0.61, 95% CI 0.41 to 0.89; stroke: 12/342 [3.5%] with metformin v 23/411 [5.6%] with diet alone; RR 0.59, 95% CI 0.29 to 1.18).

Harms

Metformin versus diet alone in overweight or obese people with type 2 diabetes:

In the RCT, metformin was associated with a similar proportion of major hypoglycaemic events to diet alone (ITT analysis; proportion of people with major hypoglycaemic events: 0.6% with metformin v 0.7% with diet alone; P value not reported).

Comment

The role of intensive glucose lowering in primary prevention of cardiovascular events remains unclear. However, such treatment clearly reduces the risk of microvascular disease and does not increase the risk of cardiovascular disease. The potential of the largest RCT in people with type 2 diabetes to show an effect of tighter glycaemic control was limited by the small difference achieved in median HbA1c between intensive and conventional treatment and the relatively low risk of cardiovascular disease. By contrast, in another primary prevention trial, a larger difference (1.9%) in median HbA1c was achieved between groups (mean HbA1c levels: 7.2% with intensive treatment v 9.1% with conventional treatment; P < 0.001), but the young age of the participants and consequent low incidence of cardiovascular events limited the power of the study to detect an effect of treatment on the incidence of cardiovascular disease.

Substantive changes

No new evidence

2006; 2006: 0601.
Published online 2006 February 1.

Intensive multiple risk factor treatment

Summary

CARDIOVASCULAR EVENTS Intensive treatment of multiple risk factors compared with conventional treatment of multiple risk factors: Intensive treatment of multiple risk factors with strict treatment goals is more effective than conventional treatment according to clinical guidelines at reducing the combined outcome of death from cardiovascular disease, non-fatal myocardial infarction, non-fatal stroke, revascularisation or amputation at 8 years in people with type 2 diabetes and microalbuminuria (very low-quality evidence ). NOTE We found no clinically important results about treating multiple risk factors compared with treating a single risk factor for cardiovascular outcomes.

Benefits

We found no systematic review or RCTs comparing treating multiple risk factors with treating a single risk factor for cardiovascular outcomes.

Intensive versus conventional treatment:

We found one RCT comparing intensive treatment of multiple risk factors versus conventional treatment of multiple risk factors. The RCT found that, compared with conventional treatment, intensive treatment of multiple risk factors in people with type 2 diabetes and microalbuminuria significantly reduced cardiovascular disease over 8 years (160 people including 39 with cardiovascular disease diagnosis, mean age 55 years; combined outcome of death from cardiovascular disease, non-fatal myocardial infarction, non-fatal stroke, revascularisation, or amputation: HR 0.47, 95% CI 0.24 to 0.73; ARR 20.0%, 95% CI 5.7% to 34.0%; NNT 5, 95% CI 3 to 18). The intensive treatment group received a stepwise treatment plan with strict treatment goals, and included behaviour modification (diet, exercise, and smoking cessation); drug treatment for aggressive management of blood glucose, blood pressure, dyslipidaemia, and microalbuminuria; and aspirin treatment for people with ischaemic cardiovascular disease. The conventional treatment group received treatment for multiple risk factors according to clinical guidelines from their general practitioner.

Harms

Intensive versus conventional treatment:

The RCT did not specifically evaluate adverse events. It found no significant difference in the incidence of minor episodes of hypoglycaemia between intensive and conventional treatment of multiple risk factors (42/80 [53%] with intensive treatment v 39/80 [49%] with conventional treatment; P = 0.5). A higher proportion of people had at least one major hypoglycaemic event requiring assistance from another person in the conventional group compared with the intensive group, but this difference was not significant (major hypoglycaemic events: 5/80 [6.3%] with intensive treatment v 12/80 [15%] with conventional treatment; P = 0.12). One person in the intensive treatment group was hospitalised for a bleeding ulcer.

Comment

Intensive versus conventional treatment:

All people in the RCT had microalbuminuria at baseline, so their cardiovascular risk would have been higher than in people with diabetes without microalbuminuria. However, the conventional treatment group received high quality care, based on guidelines, and the risk reductions from the intensive treatment might have been greater if the comparison had been with “usual care” in the community.

Substantive changes

No new evidence

2006; 2006: 0601.
Published online 2006 February 1.

Coronary artery bypass versus percutaneous transluminal angioplasty

Summary

CARDIOVASCULAR EVENTS CABG compared with PTCA without stenting: CABG is more effective at reducing the proportion of people who die or suffer Q wave myocardial infarction at 7 years ( moderate-quality evidence ). MORTALITY CABG compared with PTCA without stenting: CABG may be more effective at reducing all-cause mortality at 4 years after initial revascularisation in people with diabetes and CABG, and in people with 2 or 3 vessel coronary disease who have received at least one internal mammary graft ( low-quality evidence ).

Benefits

Coronary artery bypass graft compared with percutaneous transluminal coronary angioplasty without stenting:

One systematic review (search date 2001) found that in people with diabetes, coronary artery bypass graft (CABG) significantly reduced all cause mortality at 4.0 years after initial revascularisation compared with percutaneous transluminal coronary angioplasty (PTCA) but it found no significant difference at 6.5 years (3 RCTs: 537 people with diabetes; all cause mortality at 4.0 years: ARR 8.6%, 95% CI 2.2% to 15.0%; P < 0.01; all cause mortality at 6.5 years; ARR 3.9%, 95% CI −17.0% to + 25.0%; P = 0.71). The systematic review identified four RCTs. Two RCTS reported results at both 4.0 and 6.5 years, one at only 4.0 years, and one at only 6.5 years. Two RCTs identified by the systematic review compared CABG versus PTCA, without stenting or a glycoprotein IIb/IIIa inhibitor. The first RCT found that CABG significantly reduced the proportion of people who died or suffered Q wave myocardial infarction over a mean of 7.7 years compared with PTCA (353 people with type 1 or type 2 diabetes and 2 or 3 vessel coronary disease, mean age 62 years: 60/173 [34.7%] with CABG v 85/170 [50%] with PTCA; ARR 15%, 95% CI 5% to 26%; RR 0.69, 95% CI 0.54 to 0.89; NNT 7, 95% CI 4 to 20). This survival benefit was confined to those receiving at least one internal mammary graft. The second RCT found no significant difference between CABG or PTCA in mortality at 4 years (125 people with type 1 or type 2 diabetes, mean age 61 years; mortality: 8/63 [12.5%] with CABG v 14/62 [22.6%] with PTCA; RR 0.56, 95% CI 0.25 to 1.25; ARR 9.9%, 95% CI −3.4% to + 23.1%).

Harms

Coronary artery bypass graft compared with percutaneous transluminal coronary angioplasty without stenting:

The systematic review and the two RCTs it identified did not report on adverse effects.

Comment

None.

Substantive changes

No new evidence

2006; 2006: 0601.
Published online 2006 February 1.

Coronary artery bypass graft compared with percutaneous transluminal coronary angioplasty plus stent

Summary

CARDIOVASCULAR EVENTS CABG compared with PTCA plus stenting: CABG is more effective than PTCA plus stenting at reducing death, myocardial infarction, and revascularisation at 1 and 3 years in people with diabetes and multivessel coronary artery disease but increases the risk of stroke in the short term up to discharge ( moderate-quality evidence ).

Benefits

Coronary artery bypass graft compared with percutaneous transluminal coronary angioplasty plus stenting:

One RCT compared the effectiveness of PTCA plus stenting versus CABG in people with type 1 or type 2 diabetes. It found that at 1 year and at 3 years CABG was significantly more effective than PTCA plus stenting in preventing death, myocardial infarction, or repeat revascularisation (208 people, 15.6% with type 1 diabetes, 84.4% with type 2 diabetes, all with 2 or 3 vessel coronary disease; proportion of people event free at 1 year: 81/96 [84.4%] with CABG v 71/112 [63.4%] with PTCA plus stenting; P < 0.001; proportion of people event free at 3 years: 78/96 [81.3%] with CABG v 59/112 [52.7%] with PTCA plus stenting; P < 0.0001). Revascularisation within 3 years was required more frequently after PTCA plus stenting than after CABG (revascularisation rates: 8/96 [9.3%] with CABG v 46/112 [41%] with PTCA plus stenting; significance not assessed).

Harms

Coronary artery bypass graft compared with percutaneous transluminal coronary angioplasty plus stenting:

Initial findings from the RCT comparing PTCA plus stenting versus CABG were published in an earlier paper. It found a significant increase in stroke with CABG compared with PTCA in the short term up to discharge (208 people with type 1 and type 2 diabetes and 2 or 3 vessel coronary disease; short term risk of stroke: 4/96 [4.2%] with CABG v 0/112 [0%] with PTCA plus stent; P = 0.04). It found no significant difference between CABG and PTCA in short term risk (up to discharge) of a composite end point of death, myocardial infarction, repeat CABG, and repeat PTCA (composite outcome of death, myocardial infarction, repeat CABG, and repeat PTCA: 9/96 [9.4%] with CABG v 11/112 [9.8%] with PTCA; RR 1.05, 95% CI 0.45 to 2.42).

Comment

None.

Substantive changes

2006; 2006: 0601.
Published online 2006 February 1.

Percutaneous transluminal coronary angioplasty compared with thrombolysis

Summary

MORTALITY PTCA compared with thrombolysis: PTCA may be more effective at reducing the rate of combined death or non-fatal recurrent myocardial infarction at 30 days in diabetic people presenting with acute myocardial infarction ( low-quality evidence ).

Benefits

Percutaneous transluminal coronary angioplasty versus thrombolysis in people with acute myocardial infarction:

We found one systematic review (search date not reported) and one subsequent RCT. The systematic review pooled individual patient data from 11 RCTs comparing percutaneous transluminal coronary angioplasty (PTCA) versus thrombolysis in people with acute myocardial infarction. It found that the rate of combined death or non-fatal recurrent myocardial infarction was significantly lower with PTCA compared with thrombolysis at 30 days (11 RCTs, 367 people with unspecified diabetes and acute myocardial infarction; combined rate of death or non-fatal recurrent myocardial infarction:18/196 [9.2%] with PTCA v 33/171 [19.3%] with thrombolysis; P < 0.05). Treating 10 diabetic individuals with primary PTCA rather than thrombolysis prevented one case of death or non-fatal recurrent myocardial infarction. The subsequent RCT (395 people with ST segment elevation myocardial infarction; subgroup of 74 people with type 1 and 2 diabetes) found limited evidence of reduced mortality at median follow up of 7.5 years with PTCA compared with thrombolysis (absolute numbers not reported; HR 2.1; P = 0.04). Most study comparisons were between people with diabetes versus people without diabetes, and the study failed to report statistics comparing baseline characteristics and outcome results for the treatment subgroups, making it difficult to draw conclusions from the results.

Harms

Percutaneous transluminal coronary angioplasty versus thrombolysis in people with acute myocardial infarction:

The systematic review and subsequent RCT did not report on adverse effects.

Comment

None.

Substantive changes

No new evidence

2006; 2006: 0601.
Published online 2006 February 1.

Intracoronary stenting plus glycoprotein IIb/IIIa inhibitors

Summary

CARDIOVASCULAR EVENTS Intracoronary stenting plus glycoprotein IIb/IIIa inhibitors compared with placebo: Eptifibatide (a glycoprotein IIb/IIIa inhibitor) is more effective at reducing the composite outcome of death or myocardial infarction in people with diabetes undergoing non-urgent coronary stent implantation ( moderate-quality evidence ). Glycoprotein IIb/IIa inhibitors compared with each other: Tirofiban and abiximab are equally effective at reducing the composite outcome of death or myocardial infarction at 30 day or 6 months in people with diabetes (moderate-quality evidence). MORTALITY Intracoronary stenting plus glycoprotein IIb/IIIa inhibitors compared with placebo: Abciximab (a glycoprotein IIb/IIIa inhibitor) is more effective at reducing overall mortality at 1 year in people with diabetes undergoing percutaneous transluminal coronary angioplasty (moderate-quality evidence). Glycoprotein IIb/IIa inhibitors compared with each other: Tirofiban and abiximab are equally effective at reducing overall mortality at 1 year in people with diabetes (moderate-quality evidence).

Benefits

We found one non-systematic review of individual patient data from three RCTs and two subsequent RCTS.

Intracoronary stenting plus glycoprotein IIb/IIIa inhibitors versus placebo:

The non-systematic review pooled data from three placebo controlled trials of percutaneous coronary intervention: EPILOG, EPISTENT, and EPIC. The non-systematic review found that, compared with placebo, abciximab (a glycoprotein IIb/IIIa inhibitor) plus intracoronary stent significantly reduced overall mortality at 1 year (1462 people with type 1 and type 2 diabetes, mean age 60.9 years; mortality: 22/888 [2.5%] with abciximab v 26/574 [4.5%] with placebo; P = 0.03). The first subsequent RCT found that, compared with placebo, eptifibatide (a glycoprotein IIb/IIIa inhibitor) significantly reduced the composite outcome of death or myocardial infarction but found no significant difference for the single outcome of death at 1 year (466 people with type 1 and type 2 diabetes undergoing non-urgent coronary stent implantation, mean age 62 years; composite outcome of death or myocardial infarction: 18/232 [7.8%] with eptifibatide v 31/234 [13.4%] with placebo; HR 0.57, 95% CI 0.32 to 1.02; P = 0.001; single outcome of mortality: 3/232 [1.3%] with eptifibatide v 8/234 [3.5%] with placebo; HR 0.37, 95% CI 0.10 to 1.41; P = 0.28).

Comparison of glycoprotein IIb/IIIa inhibitors in people undergoing intracoronary stenting:

The second subsequent RCT found no significant difference between tirofiban and abciximab in composite outcomes of death or myocardial infarction at 30 days and 6 months, or overall mortality at 1 year (1117 people, 503/1117 [45%] with type 1 diabetes, 614/1117 [55%] with type 2 diabetes, all having percutaneous coronary interventions, mean age 62 years; composite outcomes of death or myocardial infarction; at 30 days: 33/560 [5.9%] with tirofiban v 29/557 [5.2%] with abciximab; HR 1.14, 95% CI 0.69 to 1.87; P = 0.6; at 6 months: 46/560 [8.2%] with tirofiban v 42/557 [7.5%] with abciximab; HR 1.09, 95% CI 0.72 to 1.65; P = 0.7; overall mortality at 1 year: 2.9% with tirofiban v 2.1% with abciximab; P = 0.4, absolute numbers not reported).

Harms

Intracoronary stenting plus glycoprotein IIb/IIIa inhibitors versus placebo:

The non-systematic review of individual patient data found that there was slightly greater bleeding in people given abciximab than in those given placebo, but none of these differences were significant (major bleeding: 4.3% with abciximab v 3.0% with placebo, P = 0.21; minor bleeding: 6.9% with abciximab v 6.3% with placebo, P = 0.66; intracranial haemorrhage: 0% with abciximab v 0.17% with placebo, P = 0.39). The first subsequent RCT did not report on any adverse events associated with eptifibatide.

Comparison of glycoprotein IIb/IIIa inhibitors in people undergoing intracoronary stenting:

The second subsequent RCT found no significant difference between abciximab and tirofiban in major bleeding events (major bleeding events: 0.5% with tirofiban v 0.7% with abciximab; P = 0.725; absolute figures not reported).

Comment

For people with diabetes undergoing percutaneous procedures, the combination of stent and glycoprotein IIb/IIIa inhibitor reduces restenosis rates and serious morbidity. It is unclear whether these adjunctive treatments would reduce the morbidity, mortality, and restenosis associated with percutaneous revascularisation procedures to the levels seen with coronary artery bypass grafting. The study comparing abciximab versus tirofiban and the study comparing eptifibatide versus placebo were both insufficiently powered to detect reductions in major cardiovascular events in the subgroups of people with diabetes.

Substantive changes

No new evidence


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