Journal of Human Hypertension (2005) 19, 185–196 & 2005 Nature Publishing Group All rights reserved 0950-9240/05 $30.00 www.nature.com/jhh ORIGINAL ARTICLE Antithrombotic therapy in hypertension: a Cochrane Systematic review DC Felmeden and GYH Lip Haemostasis, Thrombosis, and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham, UK Although elevated systemic blood pressure (BP) results on one large trial, ASA taken for 5 years reduced in high intravascular pressure, the main complications myocardial infarction (ARR, 0.5%, NNT 200 for 5 years), of hypertension are related to thrombosis rather than increased major haemorrhage (ARI, 0.7%, NNT 154), and haemorrhage. It therefore seemed plausible that use of did not reduce all cause mortality or cardiovascular antithrombotic therapy may be useful in preventing mortality. In two small trials, warfarin alone or in thrombosis-related complications of elevated BP. The combination with ASA did not reduce stroke or coronary objectives were to conduct a systematic review of the events. Glycoprotein IIb/IIIa inhibitors as well as ticlopi- role of antiplatelet therapy and anticoagulation in dine and clopidogrel have not been sufficiently eval- patients with BP, to address the following hypotheses: uated in patients with elevated BP. To conclude for (i) antiplatelet agents reduce total deaths and/or major primary prevention in patients with elevated BP, anti- thrombotic events when compared to placebo or other platelet therapy with ASA cannot be recommended active treatment; and (ii) oral anticoagulants reduce total since the magnitude of benefit, a reduction in myocar- deaths and/or major thromboembolic events when dial infarction, is negated by a harm of similar magni- compared to placebo or other active treatment. A tude, an increase in major haemorrhage. For secondary systematic review of randomised studies in patients prevention in patients with elevated BP, antiplatelet with elevated BP was performed. Studies were included therapy is recommended because the magnitude of the if they were 43 months in duration and compared absolute benefit is many times greater. Warfarin therapy antithrombotic therapy with control or other active alone or in combination with aspirin in patients with treatment. One meta-analysis of antiplatelet therapy for elevated BP cannot be recommended because of lack of secondary prevention in patients with elevated BP demonstrated benefit. Further trials of antithrombotic reported an absolute reduction in vascular events of therapy are required in patients with elevated BP. 4.1% as compared to placebo. Acetylsalicylic acid (ASA) Journal of Human Hypertension (2005) 19, 185–196. did not reduce stroke or ‘all cardiovascular events’ doi:10.1038/sj.jhh.1001807 compared to placebo in primary prevention patients with Published online 27 January 2005 elevated BP and no prior cardiovascular disease. Based Keywords: aspirin; warfarin; antithrombotic therapy Introduction and stroke by more than half.1–3 In middle and old age, there appears to be a direct relationship Although systemic (arterial) hypertension results in between the level of BP and the risk of cardiovas- high intravascular pressure, the main complications cular death without any evidence of a threshold of hypertension, that is, coronary heart disease down to a BP of at least 115/75 mmHg.4 Correspond- (CHD), ischaemic strokes and peripheral vascular ingly, BP reduction trials have shown a reduction in disease (PVD), are related to thrombosis rather than CHD by 16% and stroke by 38%. It should not be haemorrhage. The association between hypertension forgotten that hypertension is a risk factor for both and risk for stroke and CHD almost appears to have a haemorrhagic as well as ischaemic strokes. dose–response relationship, with increasing risk for 1–3 It should be recognised that some of the complica- higher blood pressures (BP). Indeed an increase in tions related to hypertension, such as heart failure or the diastolic blood pressure (DBP) by 10 mmHg is atrial fibrillation, are themselves associated with associated with an increase in CHD risk by one-third stroke and thromboembolism.5 Increasing evidence also points towards a prothrombotic or hypercoagul- Correspondence: Professor GYH Lip, Haemostasis, Thrombosis, able state conferred by the presence of hypertension, and Vascular Biology Unit, University Department of Medicine, as evident by abnormalities of coagulation,6,7 plate- City Hospital, Birmingham, UK. 6,7 8–10 E-mail: [email protected] lets and endothelial function in such patients. Received 18 October 2004; accepted 18 October 2004; published It therefore seems plausible that use of antithrom- online 27 January 2005 botic therapy may help to prevent thrombosis-related Antithrombotic therapy in hypertension DC Felmeden and GYH Lip 186 complications of hypertension.5 The antithrombotic congestive heart failure, pre-eclampsia, eclampsia or agent, aspirin, has long been used in the treatment pulmonary hypertension were excluded. and secondary prevention of many of the complica- tions of hypertension, but until recently little (c) Types of interventions information has been available on its role in the Treatment duration of at least 3 months with management of asymptomatic, hypertensive indivi- antiplatelet agents (aspirin, nonsteroidal anti-in- dual. Warfarin has also been found to be useful as flammatory drugs (NSAIDs), dipyridamole, clopido- thromboprophylaxis in hypertensive patients with grel, glycoprotein IIb/IIIa inhibitors (GPIIb/IIIa atrial fibrillation,11,12 but if blood pressures remain inhibitors) (ie ticlopidine)) or oral anticoagulants uncontrolled, such therapy carries significant risks, (warfarin and other vitamin K antagonist antic- especially from intracranial haemorrhage. oagulants) were included. Available data on con- comitant treatment were collected, where available. Objectives Types of outcome measures A systematic review of the role of antiplatelet therapy and anticoagulation was conducted in (a) Primary outcome measure(s) patients with systemic (arterial) hypertension, in- All cause mortality and cardiovascular mortality cluding those with systodiastolic hypertension, (stroke, myocardial infarction, sudden death, throm- isolated systolic hypertension and diastolic hyper- boembolic events). tension, to address the following hypotheses: (i) antiplatelet agents reduce total deaths and/or major (b) Secondary outcome measure(s) thrombotic events in patients when compared to All nonfatal cardiovascular events (stroke, myocar- placebo or other active treatment; and (ii) oral dial infarction, thromboembolic events such as anticoagulants reduce total deaths and/or major acute coronary syndrome, acute limb ischaemia, thromboembolic events in patients with hyperten- pulmonary embolism, deep vein thrombosis), as a sion when compared to placebo or other active composite end point. All major bleeding events treatment. (fatal, nonfatal) as a composite end point. A major It should be noted that antithrombotic therapy in bleed was defined as haemorrhagic stroke, or major atrial fibrillation11 and heart failure13 per se are blood loss defined as a drop in haemoglobin of considered in detail in separate Cochrane reviews. 42 g/dl with adequate hydration, or urgent transfu- In atrial fibrillation, for example, the presence of sion with final haemoglobin after equilibration of hypertension increases the risk of stroke and less than prebleed level, or orthostatic hypotension, thromboembolism, and such patients are at moder- or supine blood pressure under 90/60 mmHg. ate-to-high risk; hypertension and atrial fibrillation also commonly coexist. (c) Tertiary outcome measure(s) All cardiovascular events (sudden death, fatal, nonfatal: stroke, myocardial infarction, thromboem- bolic events, coronary revascularisation) as a com- Methods posite end point. Any interaction between risk Criteria for considering studies for this review factors for cardiovascular disease or bleeding, and concomitant treatment were analysed if appropriate (a) Types of studies data were available. Further details will be obtained Single- or double-blind randomised controlled trials from trial authors, if possible. comparing antiplatelet drugs or oral anticoagulation The search strategy for identification of studies is with control or active treatment were included. summarised in Table 1 (also see Collaborative Cohort-studies, nonrandomised controlled studies, Review Group Research Strategy17). and open-label studies were excluded. Methods of the review (b) Types of participants Patients with at least mild hypertension or isolated Two reviewers (GYHL and DCF), independently, systolic or diastolic hypertension as defined (for selected suitable trials for the inclusion of the practical reasons) by the WHO–ISH Guidelines for review. There was a review of the inclusion criteria Management of Hypertension 1999 and/or British for each question, the search strategies, the metho- Society of Hypertension Guidelines for Management dology criteria, and methods for pooling the data. of Hypertension 199914,15 were included. In trials Nonrandomised studies would not usually be help- prior to 1999, WHO–ISH guidelines valid at the time ful in a review of the effects of these drugs as any of the study/publication were used.16 Generally, a estimates of treatment effects are likely to be biased, systolic blood pressure (SBP) of X160 mmHg and/or but they have been included as they may help in a DBP of X100 mmHg
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