Antithrombotic therapy in hypertension: a Cochrane ... - Nature

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 in high intravascular pressure, the main complications of hypertension are related to thrombosis rather than haemorrhage. It therefore seemed plausible that use of antithrombotic therapy may be useful in preventing thrombosis-related complications of elevated BP. The objectives were to conduct a systematic review of the role of antiplatelet therapy and anticoagulation in patients with BP, to address the following hypotheses: (i) antiplatelet agents reduce total deaths and/or major thrombotic events when compared to placebo or other active treatment; and (ii) oral anticoagulants reduce total deaths and/or major thromboembolic events when compared to placebo or other active treatment. A systematic review of randomised studies in patients with elevated BP was performed. Studies were included if they were 43 months in duration and compared antithrombotic therapy with control or other active treatment. One meta-analysis of antiplatelet therapy for secondary prevention in patients with elevated BP reported an absolute reduction in vascular events of 4.1% as compared to placebo. Acetylsalicylic acid (ASA) did not reduce stroke or ‘all cardiovascular events’ compared to placebo in primary prevention patients with elevated BP and no prior cardiovascular disease. Based

on one large trial, ASA taken for 5 years reduced myocardial infarction (ARR, 0.5%, NNT 200 for 5 years), increased major haemorrhage (ARI, 0.7%, NNT 154), and did not reduce all cause mortality or cardiovascular mortality. In two small trials, warfarin alone or in combination with ASA did not reduce stroke or coronary events. Glycoprotein IIb/IIIa inhibitors as well as ticlopidine and clopidogrel have not been sufficiently evaluated in patients with elevated BP. To conclude for primary prevention in patients with elevated BP, antiplatelet therapy with ASA cannot be recommended since the magnitude of benefit, a reduction in myocardial infarction, is negated by a harm of similar magnitude, an increase in major haemorrhage. For secondary prevention in patients with elevated BP, antiplatelet therapy is recommended because the magnitude of the absolute benefit is many times greater. Warfarin therapy alone or in combination with aspirin in patients with elevated BP cannot be recommended because of lack of demonstrated benefit. Further trials of antithrombotic therapy are required in patients with elevated BP. Journal of Human Hypertension (2005) 19, 185–196. doi:10.1038/sj.jhh.1001807 Published online 27 January 2005

Keywords: aspirin; warfarin; antithrombotic therapy

Introduction Although systemic (arterial) hypertension results in high intravascular pressure, the main complications of hypertension, that is, coronary heart disease (CHD), ischaemic strokes and peripheral vascular disease (PVD), are related to thrombosis rather than haemorrhage. The association between hypertension and risk for stroke and CHD almost appears to have a dose–response relationship, with increasing risk for higher blood pressures (BP).1–3 Indeed an increase in the diastolic blood pressure (DBP) by 10 mmHg is associated with an increase in CHD risk by one-third Correspondence: Professor GYH Lip, Haemostasis, Thrombosis, and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham, UK. E-mail: [email protected] Received 18 October 2004; accepted 18 October 2004; published online 27 January 2005

and stroke by more than half.1–3 In middle and old age, there appears to be a direct relationship between the level of BP and the risk of cardiovascular death without any evidence of a threshold down to a BP of at least 115/75 mmHg.4 Correspondingly, BP reduction trials have shown a reduction in CHD by 16% and stroke by 38%. It should not be forgotten that hypertension is a risk factor for both haemorrhagic as well as ischaemic strokes. It should be recognised that some of the complications related to hypertension, such as heart failure or atrial fibrillation, are themselves associated with stroke and thromboembolism.5 Increasing evidence also points towards a prothrombotic or hypercoagulable state conferred by the presence of hypertension, as evident by abnormalities of coagulation,6,7 platelets6,7 and endothelial function 8–10 in such patients. It therefore seems plausible that use of antithrombotic therapy may help to prevent thrombosis-related

Antithrombotic therapy in hypertension DC Felmeden and GYH Lip 186

complications of hypertension.5 The antithrombotic agent, aspirin, has long been used in the treatment and secondary prevention of many of the complications of hypertension, but until recently little information has been available on its role in the management of asymptomatic, hypertensive individual. Warfarin has also been found to be useful as thromboprophylaxis in hypertensive patients with atrial fibrillation,11,12 but if blood pressures remain uncontrolled, such therapy carries significant risks, especially from intracranial haemorrhage.

Objectives A systematic review of the role of antiplatelet therapy and anticoagulation was conducted in patients with systemic (arterial) hypertension, including those with systodiastolic hypertension, isolated systolic hypertension and diastolic hypertension, to address the following hypotheses: (i) antiplatelet agents reduce total deaths and/or major thrombotic events in patients when compared to placebo or other active treatment; and (ii) oral anticoagulants reduce total deaths and/or major thromboembolic events in patients with hypertension when compared to placebo or other active treatment. It should be noted that antithrombotic therapy in atrial fibrillation11 and heart failure13 per se are considered in detail in separate Cochrane reviews. In atrial fibrillation, for example, the presence of hypertension increases the risk of stroke and thromboembolism, and such patients are at moderate-to-high risk; hypertension and atrial fibrillation also commonly coexist.

Methods Criteria for considering studies for this review

(a) Types of studies Single- or double-blind randomised controlled trials comparing antiplatelet drugs or oral anticoagulation with control or active treatment were included. Cohort-studies, nonrandomised controlled studies, and open-label studies were excluded. (b) Types of participants Patients with at least mild hypertension or isolated systolic or diastolic hypertension as defined (for practical reasons) by the WHO–ISH Guidelines for Management of Hypertension 1999 and/or British Society of Hypertension Guidelines for Management of Hypertension 199914,15 were included. In trials prior to 1999, WHO–ISH guidelines valid at the time of the study/publication were used.16 Generally, a systolic blood pressure (SBP) of X160 mmHg and/or a DBP of X100 mmHg was considered to be elevated and fit the criteria. Patients with atrial fibrillation, Journal of Human Hypertension

congestive heart failure, pre-eclampsia, eclampsia or pulmonary hypertension were excluded. (c) Types of interventions Treatment duration of at least 3 months with antiplatelet agents (aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), dipyridamole, clopidogrel, glycoprotein IIb/IIIa inhibitors (GPIIb/IIIa inhibitors) (ie ticlopidine)) or oral anticoagulants (warfarin and other vitamin K antagonist anticoagulants) were included. Available data on concomitant treatment were collected, where available. Types of outcome measures

(a) Primary outcome measure(s) All cause mortality and cardiovascular mortality (stroke, myocardial infarction, sudden death, thromboembolic events). (b) Secondary outcome measure(s) All nonfatal cardiovascular events (stroke, myocardial infarction, thromboembolic events such as acute coronary syndrome, acute limb ischaemia, pulmonary embolism, deep vein thrombosis), as a composite end point. All major bleeding events (fatal, nonfatal) as a composite end point. A major bleed was defined as haemorrhagic stroke, or major blood loss defined as a drop in haemoglobin of 42 g/dl with adequate hydration, or urgent transfusion with final haemoglobin after equilibration of less than prebleed level, or orthostatic hypotension, or supine blood pressure under 90/60 mmHg. (c) Tertiary outcome measure(s) All cardiovascular events (sudden death, fatal, nonfatal: stroke, myocardial infarction, thromboembolic events, coronary revascularisation) as a composite end point. Any interaction between risk factors for cardiovascular disease or bleeding, and concomitant treatment were analysed if appropriate data were available. Further details will be obtained from trial authors, if possible. The search strategy for identification of studies is summarised in Table 1 (also see Collaborative Review Group Research Strategy17). Methods of the review

Two reviewers (GYHL and DCF), independently, selected suitable trials for the inclusion of the review. There was a review of the inclusion criteria for each question, the search strategies, the methodology criteria, and methods for pooling the data. Nonrandomised studies would not usually be helpful in a review of the effects of these drugs as any estimates of treatment effects are likely to be biased, but they have been included as they may help in assessing side effects in the case of anticoagulants. Assessment of trial quality will be made in accor-


Table 1 (a) Cochrane search strategy: (a) I and (b) II (a) Cochrane Search Strategy I 1. The Cochrane Controlled Trials Register (CENTRAL) was searched using the strategy with the keywords outlined below. This was updated by searching MEDLINE 2000–2001 on Ovid using a standard RCT filter35 and EMBASE 1998–2001 using an EMBASE RCT filter.36 2. The NHS Database of Abstracts of Reviews of Effectiveness and any other relevant database were searched to identify eligible studies and review articles. Relevant foreign papers will be translated. 3. Abstracts from national and international hypertension meetings were studied to identify unpublished studies and relevant authors of these studies were contacted to obtain further details. 4. Searches of reference lists of papers were made (see Table 2). (b) Cochrane Search Strategy II 1. HYPERTENSION 2. HIGH BLOOD PRESSURE 3. BLOOD PRESSURE 4. ((#1 or #2) or #3) 5. ANTICOAGULANTS*:ME 6. ANTICOAGULANT* 7. ANTI-COAGULANT* 8. ANTITHROMBINS*:ME 9. ANTITHROMB* 10. ANTI-THROM* 11. COUMARINS*:ME 12. COUMARIN* 13. WARFARIN 14. WARFARIN*:ME 15. (((((((((#5 or #6) or #7) or #8) or #9) or #10) or #11) or #12) or #13) or #14) 16. PLATELET-AGGREGATION-INHIBITORS*:ME 17. PLATELET* 18. ANTI-PLATELET* 19. ASPIRIN*:ME 20. ASPIRIN 21. ANTI-INFLAMMATORY-AGENTS-NON-STEROIDAL*:ME 22. (NONSTEROID* near ANTIINFLAMM*) 23. (NON-STEROID* near ANTIINFLAM*) 24. (NONSTEROID* near ANTIINFLAM*) 25. (NON-STEROID* near ANTI-INFLAM*) 26. (NONSTEROID* near ANTI-INFLAM*) 27. NSAID* 28. TICLOPIDINE 29. CLOPIDOGREL 30. DIPYRIDAMOL 31. ((((((((((((((#16 or #17) or #18) or #19) or #20) or #21) or #22) or #23) or #24) or #25) or #26) or #27) or #28) or #29) or#30) 32. (#4 and #15) 33. (#31 and #32)

dance with guidelines in the Cochrane Handbook,18 with consideration of adequacy of randomisation, degree of blinding, and losses to follow-up for each trial. In the rare instances where the two reviewers (GYHL and DCF) disagreed over the grading and inclusion of the studies, recourse to a third reviewer was made. Appropriate statistical analyses were applied (eg type of therapeutic effect measure, choice of fixed or random effects model, testing of heterogeneity, etc). The outcome measure was reported as relative hazard rate (RR) with 95% confidence interval (CI).

Results Description of studies

A total of 2482 potentially relevant publications were initially identified and screened for retrieval:

1527 papers were excluded because of the coexistence of atrial fibrillation or generally lack of suitability of the study (see Quorum diagram, Figure 1). Finally, 946 studies were considered to be eligible for inclusion in this review, and in total 887 nonrandomised studies were excluded. Among the studies evaluating NSAIDs (including aspirin), clopidogrel and ticlopidine, 33 studies were not included for further analysis because of the short duration of the studies and in 13 publications, we were unable to obtain data of the hypertensive subgroup; thus, nine potentially appropriate randomised controlled trials remained evaluating the effects of these drugs in hypertensive patients. One study was double reported, but two different definitions for hypertension were used: patients with SBP 4145 mmHg,19 or patients treated with antihypertensive drugs at entry or during the trial.20 Both sets of data reported on different aspects of antithrombotic therapy in hypertensive Journal of Human Hypertension


Potentially relevant publications identified and screened for retrieval: 2130 (NS) 284 (WA) 68 (GP)

Papers retrieved for more detailed evaluation: 707 182 66

(NS) (WA) (GP)

1423 102 2

1 2

(NS) (WA) (GP)

(NS) (WA) (GP)

Reasons for exclusion: Non-randomised Lack of 3 month follow up Multifactorial intervention unable to obtain data of hypertensive subgroup other Total:

Papers included: 9 1 0

Paper excluded on the basis of the title and abstract (generally due to lack of suitability of study design or intention)

NS 649 33 1

WA 178 0 0

GP 60 5 0

13 2 ___ 698

3 0 ___ 181

1 0 ___ 66

Papers coalesced into RCTs (further publications of single studies grouped):

Potentially appropriate RCTs (with or without appropriate outcome data): 8+1 1 0

(NS) (WA) (GP) RCTs excluded in systematic review, due to unusable outcome data: 4

RCTs with useful outcome data included in the review 4+1 1 0

(NS) (WA) (GP)

Abbrevation NS: Non-steroidal anti-inflammatory drugs including aspirin, clopidogrel and ticlopidine WA: Warfarin GP: Glycoprotein IIb/IIIa inhibitor

Figure 1 Quorum diagram.

subgroups. These data were considered separately and duplicated data were not considered twice. In three studies evaluating warfarin, detailed data on the hypertensive patients were not made available to us and had to be excluded.21–23 One study remained for further analysis.24 Five studies investigating ticlopidine and glycoprotein IIb/IIIa inhibitors and their impact on cardiovascular and haemorrhagic events lacked sufficient follow-up data.25–29 A further publication was excluded due to the inability to acquire the relevant data.30 Most of the excluded trials were less than 1-month duration; in particular, the five GPIIb/IIIa inhibitor Journal of Human Hypertension

trials were only observing the effects over a few days. We did not consider that this observational period would be sufficient to make any meaningful statements about the prevention of thromboembolic events in hypertensive patients. Furthermore, the NSAID trials assessed the effects on BP itself rather than thromboembolic complication.

Methodological quality of included studies

The only randomised placebo-controlled trial designed to investigate the effects of antithrombotic


therapy (aspirin) on cardiovascular events and haemorrhagic complication in treated hypertensive patients was the large HOT study (Hypertension Optimal Treatment randomised trial31). This trial was a primary prevention trial in patients with elevated BP (DBP between 100 and 115 mmHg). The aspirin component of this trial was a double-blind placebo-controlled design. Major cardiovascular events were defined as fatal and nonfatal myocardial infarction, fatal and nonfatal stroke and other cardiovascular deaths. Silent myocardial infarction was defined as new Q or QS waves without clinical signs of myocardial infarction. Among the other included studies, we tried to obtain further information from the authors. In the majority of the studies, we were unable to retrieve the data, which was largely due to the fact of the length of time since publication of the original trials. However, details were successfully requested from two studies24,32 and one study having published a subgroup analysis with a different definition hypertension (SBP4145 mmHg19) than in the data set provided from the original trial.20 Both sets of data have been considered separately. These trials are summarised in Table 2. For the characteristics of the excluded studies of the Cochrane review, see Table 3. CAPRIE (Clopidogrel vs Aspirin in Patients at Risk of Ischaemic Events32) was a secondary prevention trial in patients with recent ischaemic stroke, recent myocardial infarction (MI) or symptomatic peripheral arterial disease. End points were all-cause mortality, vascular death, myocardial infarction, ischaemic or haemorrhagic stroke, allcause rehospitalisation, hospitalisation for ischaemic events (unstable angina, TIA, limb ischaemic) or for bleeding events. Huynh et al24 reported a secondary prevention trial in patients with unstable angina or non-ST elevation MI and prior CABG. Patients with uncontrolled systemic hypertension (4180/95 mmHg) were excluded. Randomisation: warfarin (INR 2.0–2.5) þ placebo; aspirin 80 mg OD þ placebo; or warfarin þ aspirin; double-blind. Definition of end points: composite end point of all-cause mortality, MI or unstable angina requiring hospital admission. This study was underpowered by a low event rate to detect a difference between treatment groups. The Thrombosis Prevention Trial19,20 was a primary prevention trial in patients with high risk of ischaemic heart disease. Data for subgroup analysis of patients treated with antihypertensive medication at entry or during trial were reported in a subsequent publication. Definition of end points: fatal and nonfatal events (ie, coronary death and fatal and nonfatal myocardial infarction). Stroke was a secondary end point, with results for thrombotic and haemorrhagic events to be distinguished as far as possible.

Aspirin vs placebo

(a) All-cause mortality All-cause mortality was reported in one trial (HOT).31 In the HOT study, mortality was 3.0% in the aspirin-treated patients compared with 3.2% in the placebo-control group and was not different (P ¼ 0.36). The cardiovascular and noncardiovascular mortality, were also not different. Data relating to all cause mortality from Thrombosis Prevention Trial was not available.20 (b) Cardiovascular events Cardiovascular events were evaluated in two studies.20,31 In the HOT trial, aspirin reduced MI (ARR ¼ 0.5%, NNT ¼ 200) and major cardiovascular events (ARR ¼ 0.57%, NNT ¼ 176) as compared to placebo. However, when all cardiovascular events including silent MI were considered, the reduction failed to reach statistical significance. Similarly, in the Thrombosis Prevention Trial, no significant difference was observed in the cardiovascular events in the hypertensive subgroup between the aspirin, 8.5% and placebo, 7.5%.20 When the results of both studies were pooled for all cardiovascular events, there was no significant difference with aspirin as compared to placebo (OR 0.93; 95% CI: 0.82–1.06). (c) Stroke Ischaemic strokes were reported in two trials.20,31 In the pooled results, there was no significant difference between the aspirin and the control group (OR 0.94; 95% CI: 0.76–1.17). (d) Haemorrhage The haemorrhagic effects of aspirin alone when compared to placebo were evaluated in the HOT study.31 There was a significant increase in major bleeds (ARI ¼ 0.65%, NNH ¼ 154) and minor bleeds (ARI ¼ 0.73%, NNH ¼ 137) with aspirin as compared to placebo. The differences in these events were mainly explained by increased gastrointestinal (72 vs 34 for major bleeds and 30 vs 18 for minor bleeds) and nasal bleeds (22 vs 12 for major bleeds and 66 vs 24 for minor bleeds) in the aspirin group. However, there was no significant difference in fatal haemorrhagic events (seven (aspirin) vs eight (placebo)).

Aspirin vs clopidogrel

The composite end point of stroke, MI or vascular death has been evaluated in one study in hypertensive patients was not different in patients taking aspirin, 12.1% as compared to clopidogrel, 11.0%.32 Data on all-cause mortality, cardiovascular mortality, all cardiovascular events, stroke, myocardial infarction or haemorrhagic events were not reported. Journal of Human Hypertension

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Table 2 Characteristics of included studies Study CAPRIE 199632

Participants

Interventions

Outcomes

Randomised, blinded, international

Previous stroke, MI or symptomatic PVD

Aspirin 325 mg vs clopidogrel 75 mg

Stroke, MI, vascular death

PROBE, placebo double-blind for aspirin, DBPo90 mmHg DBPo85 mmHg DBPo80 mmHg

19 193 pt with DBP 105–115 mmHg age 50–80 years

ACE or BB felodipine diuretic; aspirin 75 mg or placebo

Multi centre/national

A

135 patients with prior CABG with UA or nonST, elevation MI, 5499 men aged 45–69 years increased risk of CHD

Aspirin +placebo or warfarin+placebo or aspirin +warfarin

Major CV events, +silent MI, All MI, All MI+silent MI, All CVA, CV mortality, tot mortality; fatal bleed, nonfatal bleed, minor bleed All-cause mortality, MI, UA, reperfusion procedure

INR 2–2.5

A

Aspirin 75 mg vs placebo (+warfarin vs placebo)

1. Fatal and nonfatal CHD 2. CVA

Subgroup analysis of aspirin group, according to SBP: o130, 130–145, 4145 mmHg on antihypertensive meds during trial

A

Aspirin 75 mg vs placebo+warfarin vs placebo

1. Fatal and non-fatal CHD 2. CVA

Huynh et al24

Meade et al19

Double-blind, placebocontrolled

Thrombosis Prevention Trial 199820

Double-blind, placebocontrolled

5499 men aged 45–69 years increased risk of CHD

Notes

Allocation A

A

CAPRIE: Clopidogrel vs aspirin in patients at risk of ischaemic events; HOT: Hypertension Optimal Treatment randomised trial; MI: myocardial infarction; PROBE: prospective, randomised, open, blinded end point, PVD: peripheral vascular disease; SBP: systolic blood pressure; DBP: diastolic blood pressure; CHD coronary heart disease; CVA: cerebrovascular accident; CV: cardiovascular; UA: unstable angina; INR: International Normalised Ratio; CABG: coronary artery bypass graft.

Antithrombotic therapy in hypertension DC Felmeden and GYH Lip

HOT (Hanson et al31)

Methods


Table 3 Characteristics of excluded studies of the Cochrane review Reasons for exclusion

Study references

Unable to obtain data for hypertensive group

21, 22, 23, 26, 30, 33, 37, 38, 39, 44, 45, 51, 56, 57, 64, 78, 81, 84, 88, 95 27, 29, 43, 46, 48, 49, 50, 53, 54, 55, 58, 60, 61, 62, 65, 66, 68, 69, 70, 71, 72, 73, 74, 76, 79, 80, 82, 85, 89, 90, 91, 92, 93, 94, 97 25, 40, 41, 42, 52, 63, 67, 75, 77, 86, 87 28, 59,

Treatment duration o3 months Open label, not randomised, observational or retrospective study Unsuitable end points Other Calculation of the effect of ‘Clopidogrel vs placebo’ Control group treated with corticosteroids, methotrexate and cyclosporin—unsuitable for this analysis as effecting BP and other variables Patient on antihypertensives excluded, remaining patients SBP 119.4(3.9) mmHg and DBP 73.5(2.4) mmHg

47 83 96

BP, blood pressure; SBP, systolic BP; DBP, diastolic BP.

Aspirin and/or warfarin 24

This study by Huynh et al with a low event rate was underpowered to detect a difference in the hypertensive subgroup of patients. Data on all-cause mortality, cardiovascular mortality or all cardiovascular events were not reported. This study evaluated the effects of aspirin and warfarin alone or in combination on the composite end point of death and cardiovascular events (MI, stroke, angina, cardiac arrest and revascularisation procedures). There were no significant differences in this composite end point in the hypertensive subgroup (aspirin 2/14, warfarin 5/15, aspirin þ warfarin 5/14). There was no significant difference in the haemorrhagic complications (ASA, 0/14, warfarin, 0/15, aspirin þ warfarin, 1/14).24 The single haemorrhagic event occurred in the group treated with aspirin and warfarin.

Warfarin vs no warfarin

In the Thrombosis Prevention Trial,20 data on allcause mortality, cardiovascular mortality or all cardiovascular events were not reported. (a) Coronary events Coronary events (coronary death, fatal and nonfatal myocardial infarction) were evaluated in one study comparing warfarin and warfarin plus aspirin (warfarin group) vs aspirin and placebo (no-warfarin group) in hypertensive patients.20 Coronary events were not different in the warfarin group, 7.4 vs 8.6% in no-warfarin group. In the same study, the hypertensive subgroup was analysed according to the occurrence of strokes (excluding haemorrhagic strokes). Strokes were not different with warfarin (aspirin plus warfarin or warfarin alone), 2.8%, compared to no-warfarin group, 3.2%. Combined cardiovascular events (stroke and coronary events)

were not different between warfarin and no-warfarin groups. (b) Haemorrhagic strokes Data for haemorrhagic strokes were only available in pooled form combining warfarin and aspirin compared to placebo.20 No significant difference between the two arms was found. No haemorrhagic strokes occurred in the placebo group (N ¼ 342), but four such events were observed in the group taking warfarin and aspirin (N ¼ 338). Owing to the low event rate, no meaningful statistical analysis was possible. Safety data

In patients of 60 years or older with isolated systolic hypertension (SBP4160–219 mmHg and DBPo95 mmHg, patients never taking NSAIDs (n ¼ 2882) were compared with patients on chronic NSAID intake (n ¼ 861), defined as reporting NSAID intake on at least 50% of the patient forms.98 There was a tendency towards lower mortality (RR (95% CI), 0.77 (0.56–1.06)) and higher incidence of bleeding 1.13 (0.63–2.05) with chronic NSAID intake.

Discussion Hypertension potentially confers a prothrombotic state.6,7,10 Antithrombotic drugs such as aspirin, dipyridamole, clopidogrel, ticlopidine, GPIIb/IIIa inhibitors and oral anticoagulants may have a particular role in the treatment of hypertensive patients. This antithrombotic action might prevent death and/or cardiovascular thrombotic events. However, data from previous studies suggest that antithrombotic therapy is associated with an increase in haemorrhagic complications. This risk might be amplified in hypertensive patients, Journal of Human Hypertension


potentially reversing the benefit/harm ratio for this therapy. The primary analysis in the present review is based on four high-quality prospective randomised double-blind controlled trials. Two of these trials evaluated the effects of aspirin as compared to placebo,20,31 while one trial compared the effects of aspirin, warfarin and aspirin plus warfarin.24 A further trial investigated the outcome of aspirin vs clopidogrel.32 Currently, there is only one large RCT with antithrombotic therapy that recruited solely hypertensive patients.31 Several of the potentially suitable trials enrolled up to 66% of patients with hypertension, but despite relentless efforts, we were unable to obtain the data for the subgroup of hypertensive patients. One large meta-analysis of prolonged antiplatelet therapy assessed outcome data in 142 trials in ‘high-risk’ patients (some vascular disease or other conditions implying an increased risk of occlusive vascular disease) and three trials in ‘lowrisk’ patients.33 I was able to get data on the subgroup of hypertensive patients with DBP of 490 mmHg from 29 of these trials. They have reported these data on the composite outcome measure major vascular events (defined as nonfatal myocardial infarction, nonfatal stroke or vascular deaths). Unfortunately, it was not possible to get further information from the authors as to which trials were involved or the details of the data from the individual trials. Thus, these data could not be included in the present analysis. The Antiplatelet Trialists’ Collaboration meta-analysis of prolonged antiplatelet therapy compared to placebo in 100 000 patients with or without hypertension reduced all-cause mortality (ARR ¼ 1.1%, NNT ¼ 91) which was mostly due to vascular deaths (ARR ¼ 1.0%, NNT ¼ 100); nonfatal myocardial infarction (ARR ¼ 1.1%, NNT ¼ 91); nonfatal stroke (ARR ¼ 0.5%, NNT ¼ 200); and the composite outcome measure major vascular events (ARR ¼ 2.4%, NNT ¼ 42). Haemorrhagic events were not reported. The benefit of antiplatelet therapy in secondary prevention in patients with or without hypertension has been established by the Antiplatelet Trialists’ Collaboration meta-analysis. In the hypertensive subgroup of 29 trials (10 600 patients), antiplatelet therapy significantly reduced major vascular events (ARR ¼ 4.1%, NNT ¼ 25). Allcause mortality, cardiovascular mortality, nonfatal MI, nonfatal stroke and haemorrhagic events were not reported in the hypertensive subgroup. These data suggest that the absolute benefit for antiplatelet therapy for secondary prevention is greater in patients with hypertension than in patients without hypertension. The HOT trial demonstrated a significant reduction by aspirin as compared to placebo in major cardiovascular events (ARR ¼ 0.6%, NNT ¼ 176) and myocardial infarction (ARR ¼ 0.5%, NNT ¼ 200).31 This benefit for primary prevention in hypertensive Journal of Human Hypertension

patients is substantially lower than that seen in the Antiplatelet Trialists’ Collaboration analysis for secondary prevention. Furthermore, strokes, cardiovascular and all-cause mortality were not significantly different in the HOT trial. In particular, aspirin did not affect the stroke rate, and as not all patients had CT scans, the proportion of ischaemic and haemorrhagic strokes in HOT is uncertain. There was also a significant increase in major bleeds, ARI ¼ 0.7%, NNH ¼ 200) and minor bleeds, ARI ¼ 0.7%, NNH ¼ 137). The differences in these events were mainly explained by increased gastrointestinal (72 vs 34 for major bleeds and 30 vs 18 for minor bleeds) and nasal bleeds (22 vs 12 for major bleeds and 66 vs 24 for minor bleeds) in the aspirin vs placebo group. However, there was no significant difference in fatal haemorrhagic events (seven in the aspirin vs eight in placebo group). Since the magnitude of the harm is similar to the benefit, aspirin cannot be recommended for primary prevention in patients with hypertension. The Antiplatelet Trialists’ Collaboration metaanalysis of the three primary prevention trials based on 28 000 patients also showed no significant difference in all-cause mortality, nonfatal stroke or cardiovascular events. The significant decrease in nonfatal MI (ARR ¼ 0.5%, NNT ¼ 200) in antiplatelet group compared to placebo is similar to that seen in the HOT trial. Haemorrhagic events were not reported in the low-risk patient population. Clopidogrel might be an alternative antithrombotic therapy to aspirin, although there has been no head-to-head of aspirin vs clopidogrel in hypertensive patients. The subgroup analysis of hypertensive patients only demonstrated a nonsignificant trend towards a decreased composite end point of stroke, MI or vascular death.32 This would suggest that in hypertensive patients who are intolerant of aspirin that clopidogrel may be an effective alternative. However, further studies are required comparing clopidogrel and aspirin in hypertensive patients. Rigorous and aggressive BP control is advisable when using antithrombotic therapy in hypertension, as suggested by the Thrombosis Prevention Trial.20 A subgroup analysis from this trial showed that treatment with aspirin compared to placebo reduces major cardiovascular events particularly strokes in people with normal (SBP 130–145 mmHg) or even low BP (SBPo130 mmHg), whereas this risk reduction was not seen in patients with SBP 4145 mmHg.19 This suggests that the benefit of aspirin therapy may occur primarily in patients with well-controlled BP. There are only limited data available on warfarin as an antithrombotic agent in hypertension. Owing to small numbers, there was no significant difference in hypertensives when comparing warfarin with placebo or aspirin or the combination of aspirin and warfarin with regard to cardiovascular events or haemorrhagic complication. However, there is a nonsignificant trend suggesting that


warfarin is inferior to aspirin in preventing thromboembolic events in this group. Warfarin seems to be also associated with a higher rate of haemorrhagic complications. Based on currently available data, warfarin therapy in hypertension cannot be recommended. There were no data available from subgroup analyses of hypertensive patients treated with glycoprotein IIb/IIIa inhibitors. However, oral glycoprotein IIb/IIIa inhibitors have failed to demonstrate an advantage over aspirin after percutaneous coronary revascularisation.34 These patients are at high risk of thromboembolic events.

Conclusion For primary prevention in hypertensive patients, antiplatelet therapy with aspirin cannot be recommended since the magnitude of benefit of a reduction in myocardial infarction is similar to the magnitude of harm of an increased risk of major haemorrhagic events. For secondary prevention in hypertensive patients, antiplatelet therapy is recommended, as the magnitude of the benefit is greater than that in a nonhypertensive population. Antithrombotic therapy with warfarin alone or in combination with aspirin in patients with hypertension cannot be recommended because of lack of effectiveness in reducing cardiovascular events as well as a trend towards increased haemorrhagic events. Glycoprotein IIb/IIIa inhibitors as well as ticlopidine and clopidogrel have not been sufficiently evaluated in order to recommend their use in hypertensive patients. As we have excluded patients with atrial fibrillation from this analyses, the recommendations do not apply to patients in atrial fibrillation with or without hypertension. This review adds to the Antiplatelet Trialists’ Collaboration meta-analysis as we include the specific designed prospective placebo-controlled HOT trial with information on bleeding complications and correction of the estimated benefit on cardiovascular events of aspirin use in hypertension. This review is also published in the Cochrane Database of Systematic Reviews, as follows: Lip GYH, Felmeden DC. Antiplatelet agents and anticoagulants for hypertension. Cochrane Database Syst Rev. 2004;(3):CD003186.

Acknowledgements We acknowledge the support of the Sandwell & West Birmingham Hospitals NHS Trust Research and Development Program for the Haemostasis, Thrombosis and Vascular Biology Unit. We thank our colleagues in the Cochrane Hypertension Group for helpful comments and advice, as well as assisting with the detailed Cochrane peer review process.

Duality of interest Our unit undertakes clinical trials of antithrombotic therapy in cardiovascular disease and stroke, and has received research funding from various pharmaceutical companies involved in thrombosis and antithrombotic therapy.

References 1 Collins R, MacMahon S. Blood pressure, antihypertensive drug treatment and the risks of stroke and of coronary heart disease. Br Med Bull 1994; 50: 272–298. 2 Collins R et al. Blood pressure, stroke, and coronary heart disease. Part 2, Short-term reductions in blood pressure: overview of randomised drug trials in their epidemiological context. Lancet 1990; 335: 827–838. 3 Collins R et al. Blood pressure, stroke, and coronary heart disease. Part 1, Prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet 1990; 335: 765–774. 4 Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002; 360: 1903–1913. 5 Lip GYH, Edmunds E, Beevers DG. Should patients with hypertension receive antithrombotic therapy? J Intern Med 2001; 249: 205–214. 6 Lip GYH, Beevers DG. Abnormalities of rheology and coagulation in hypertension. J Hum Hypertens 1994; 8: 693–702. 7 Lee AJ. The role of rheological and haemostatic factors in hypertension. J Hum Hypertens 1997; 11: 767–776. 8 Vanhoutte PM. Endothelial dysfunction in hypertension. J Hypertens Suppl 1996; 14: S83–S93. 9 Lip GY, Blann AD. Does hypertension confer a prothrombotic state? Virchow’s triad revisited. Circulation 2000; 101: 218–220. 10 Lip GYH et al. Relationship of endothelium, thrombogenesis, and haemorrheology in systemic hypertension to ethnicity and left ventricular hypertrophy. Am J Cardiol 1997; 80: 1566–1571. 11 Segal JB et al. Anticoagulants or antiplatelet therapy for non-rheumatic atrial fibrillation and flutter (Cochrane Review). In: Cochrane Library, Issue 2. Update Software: Oxford, 2001 CD001938. 12 SPAF II Study. Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation: Stroke Prevention in Atrial Fibrillation II Study. Lancet 1994; 343: 687–691. 13 Lip GYH, Gibbs CR. Antiplatelet agents versus control or anticoagulation for heart failure in sinus rhythm (Cochrane Review). In: The Cochrane Library, Issue 4. John Wiley & Sons, Ltd: Chichester, UK, 2001 CD003333. 14 WHO–ISHGMH. World Health Organization–International Society of Hypertension Guidelines for the management of hypertension. Guidelines Subcommittee. J Hypertens 1999; 17: 151–183. 15 Ramsay L et al. Guidelines for management of hypertension: report of the third working party of the British Hypertension Society. J Hum Hypertens 1999; 13: 569–592. Journal of Human Hypertension


16 WHO Guidelines Sub-Committee. Guidelines for the management of mild hypertension: memorandum from a World Health Organization/International Society of Hypertension meeting. J Hypertens 1993; 11: 905–918. 17 Clarke M, Oxman AD (eds). Cochrane Reviewers’ Handbook 4.2.0 [updated March 2003]. In: The Cochrane Library, Issue 2, 2003. Oxford: Update Software. 18 Mulrow CD, Cook DJ, Davidoff F. Systematic reviews: critical links in the great chain of evidence. Ann Intern Med 1997; 126: 389–391. 19 Meade TW, Brennan PJ. Determination of who may derive most benefit from aspirin in primary prevention: subgroup results from a randomised controlled trial. BMJ 2000; 321: 13–17. 20 The Medical Research Council’s General Practice Research Framework. Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. Lancet 1998; 351: 233–241. 21 O’Connor CM et al. Comparison of two aspirin doses on ischemic stroke in post-myocardial infarction patients in the warfarin (Coumadin) Aspirin Reinfarction Study (CARS). Am J Cardiol 2001; 88: 541–546. 22 Mohr JP et al. A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N Engl J Med 2001; 345: 1444–1451. 23 The Stroke Prevention in Reversible Ischemia Trial (SPIRIT) Study Group. A randomized trial of anticoagulants versus aspirin after cerebral ischemia of presumed arterial origin. Ann Neurol 1997; 42: 857–865. 24 Huynh T et al. Aspirin, warfarin or the combination for secondary prevention of coronary events in patients with acute coronary syndromes and prior coronary artery bypass surgery. Circulation 2001; 103: 3069–3074. 25 Schuhlen H et al. Incidence of thrombotic occlusion and major adverse cardiac events between two and four weeks after coronary stent placement: analysis of 5,678 patients with a four-week ticlopidine regimen. J Am Coll Cardiol 2001; 37: 2066–2073. 26 Thel MC et al. Clinical risk factors for ischemic complications after percutaneous coronary interventions: results from the EPIC trial. The EPIC Investigators. Am Heart J 1999; 137: 264–273. 27 Kleiman NS 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. 28 Novo S et al. Effects of captopril and ticlopidine, alone or in combination, in hypertensive patients with intermittent claudication. Int Angiol 1996; 15: 169–174. 29 Finelli C et al. Ticlopidine lowers plasma fibrinogen in patients with polycythaemia rubra vera and additional thrombotic risk factors. A double-blind controlled study. Acta Haematol 1991; 85: 113–118. 30 Hass WK, et al., for the Ticlopidine Aspirin Stroke Study Group. A randomised trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients. N Engl J Med 1989; 321: 501–507. 31 Hansson L, et al., for the HOT Study Group. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principle results of Journal of Human Hypertension

32

33

34

35 36

37 38

39 40

41

42 43

44

45

46

47

the Hypertension Optimal Treatment randomised trial. Lancet 1998; 351: 1755–1762. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348: 1329–1339. Antiplatelet Trialists’ Collaboration. Collaborative overview of randomised trials of antiplatelet therapy—I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists’ Collaboration. BMJ 1994; 308: 81–106. O’Neill WW et al. Long-term treatment with a platelet glycoprotein-receptor antagonist after percutaneous coronary revascularization. EXCITE Trial Investigators. Evaluation of oral xemilofiban in controlling thrombotic events. N Engl J Med 2000; 342: 1316–1324. Dickersin K, Herxheimer A. Introduction: the quality of the medical evidence: is it good enough? Int J Technol Assess Health Care 1996; 12: 187–189. Lefebvre C, McDonald S. Development of a sensitive search strategy for reports of randomized controlled trials in EMBASE. Paper presented at the Fourth International Cochrane Colloquium, Adelaide, Australia, 20–24 October 1996. Ajani UA et al. Alcohol consumption and risk of coronary heart disease by diabetes status. Circulation 2000; 102: 500–505. Bhatt DL et al. Reduction in the need for hospitalization for recurrent ischemic events and bleeding with clopidogrel instead of aspirin. CAPRIE investigators. Am Heart J 2000; 140: 67–73. Bhatt DL et al. Superiority of clopidogrel versus aspirin in patients with prior cardiac surgery. Circulation 2001; 103: 363–368. Califf RM et al. Prediction of 1-year survival after thrombolysis for acute myocardial infarction in the global utilization of streptokinase and TPA for occluded coronary arteries trial. Circulation 2000; 101: 2231–2238. Caravaca F et al. Haemodynamic changes induced by the correction of anaemia by erythropoietin: role of antiplatelet therapy. Nephrol Dial Transplant 1995; 10: 1720–1724. Cook ME et al. Comparative effects of nabumetone, sulindac, and ibuprofen on renal function. J Rheumatol 1997; 24: 1137–1144. Cusson JR et al. Effect of ketoprofen on blood pressure, endocrine and renal responses to chronic dosing with captopril in patients with essential hypertension. Blood Press 1992; 1: 162–167. Drapkin A, Merskey C. Anticoagulant therapy after acute myocardial infarction. Relation of therapeutic benefit to patient’s age, sex, and severity of infarction. JAMA 1972; 222: 541–548. Forbes CD, for the ESPS Investigators. Secondary stroke prevention with low-dose aspirin, sustained release dipyridamol alone and in combination. Thromb Res 1998; 92: S1–S6. Ferri C et al. Enhanced blood pressure response to cyclooxygenase inhibition in salt-sensitive human essential hypertension. Hypertension 1993; 21(6 Part 1): 875–881. Fisher LD, Gent M, Buller HR. Active-control trials: how would a new agent compare with placebo? A method illustrated with clopidogrel, aspirin, and placebo. Am Heart J 2001; 141: 26–32.


48 Forbes CD et al. Clopidogrel compatibility with concomitant cardiac co-medications: a study of its interactions with a beta-blocker and a calcium uptake antagonist. Semin Thromb Hemost 1999; 25: 55–60. 49 Furey SA, Vargas R, McMahon FG. Renovascular effects of nonprescription ibuprofen in elderly hypertensive patients with mild renal impairment. Pharmacotherapy 1993; 13: 143–148. 50 Gurwitz JH et al. The impact of ibuprofen on the efficacy of antihypertensive treatment with hydrochlorothiazide in elderly persons. J Gerontol A Biol Sci Med Sci 1996; 51: M74–M79. 51 Harker LA, Boissel JP, Pilgrim AJ, Gent M. Comparative safety and tolerability of clopidogrel and aspirin: results from CAPRIE. CAPRIE Steering Committee and Investigators. Clopidogrel versus aspirin in patients at risk of ischaemic events. Drug Saf 1999; 21: 325–335. 52 Harpaz D et al. Effect of aspirin on the mortality in women with symptomatic or silent myocardial infarction. Am J Cardiol 1996; 78: 1215–1219. 53 Hartmann D et al. Study on the possible interaction between tenoxicam and atenolol in hypertensive patients. Arzneimittelforschung 1995; 45: 494–498. 54 Harvey PJ et al. Effect of indomethacin on blood pressure control during treatment with nitrendipine. Blood Press 1995; 4: 307–312. 55 Hermida RC et al. Influence of aspirin usage on blood pressure: dose and administration-time dependencies. Chronobiol Int 1997; 14: 619–637. 56 Herskovits E et al. Preventive treatment of cerebral transient ischemia: comparative randomized trial of pentoxifylline versus conventional antiaggregants. Eur Neurol 1985; 24: 73–81. 57 Hess H, Mietaschk A, Deichsel G. Drug-induced inhibition of platelet function delays progression of peripheral occlusive arterial disease. A prospective double-blind arteriographically controlled trial. Lancet 1985; 1: 415–419. 58 Houston MC et al. The effects of nonsteroidal antiinflammatory drugs on blood pressures of patients with hypertension controlled by verapamil. Arch Intern Med 1995; 155: 1049–1054. 59 Houtsmuller AJ et al. The influence of teiclopidine on the natural course of retinal vein occlusion. Agents Actions Suppl 1984; 15: 219–229. 60 Johnson AG et al. Potential mechanisms by which nonsteroidal anti-inflammatory drugs elevate blood pressure: the role of endothelin-1. J Hum Hypertens 1996; 10: 257–261. 61 Klassen D et al. Assessment of blood pressure during treatment with naproxen or ibuprofen in hypertensive patients treated with hydrochlorothiazide. J Clin Pharmacol 1993; 33: 971–978. 62 Klassen DK, Jane LH, Young DY, Peterson CA. Assessment of blood pressure during naproxen therapy in hypertensive patients treated with nicardipine. Am J Hypertens 1995; 8: 146–153. 63 Lee IM et al. Exercise and risk of stroke in male physicians. Stroke 1999; 30: 1–6. 64 Lemak NA, Fields WS, Gary Jr HE. Controlled trial of aspirin in cerebral ischemia: an addendum. Neurology 1986; 36: 705–710. 65 Magagna A et al. Indomethacin raises blood pressure in untreated essential hypertensives: a double-blind randomly allocated study versus placebo. J Hypertens Suppl 1991; 9: S242–S243.

66 Magagna A et al. Hemodynamic and humoral effects of low-dose aspirin in treated and untreated essential hypertensive patients. Blood Press 1994; 3: 236–241. 67 Maggioni AP et al. The risk of stroke in patients with acute myocardial infarction after thrombolytic and antithrombotic treatment. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico II (GISSI-2), and The International Study Group. N Engl J Med 1992; 327: 1–6. 68 Mehta SR et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001; 358: 527–533. 69 Mills EH, Whitworth JA, Andrews J, Kincaid-Smith P. Non-steroidal anti-inflammatory drugs and blood pressure. Aust N Z J Med 1982; 12: 478–482. 70 Minuz P, Barrow SE, Cockcroft JR, Ritter JM. Effects of non-steroidal anti-inflammatory drugs on prostacyclin and thromboxane biosynthesis in patients with mild essential hypertension. Br J Clin Pharmacol 1990; 30: 519–526. 71 Minuz P et al. Amlodipine and haemodynamic effects of cyclo-oxygenase inhibition. Br J Clin Pharmacol 1995; 39: 45–50. 72 Morgan T, Anderson A. Interaction of indomethacin with felodipine and enalapril. J Hypertens Suppl 1993; 11(Suppl 5): S338–S339. 73 Morgan TO, Anderson A, Bertram D. Effect of indomethacin on blood pressure in elderly people with essential hypertension well controlled on amlodipine or enalapril. Am J Hypertens 2000; 13: 1161–1167. 74 Nawarskas JJ, Townsend RR, Cirigliano MD, Spinler SA. Effect of aspirin on blood pressure in hypertensive patients taking enalapril or losartan. Am J Hypertens 1999; 12(8 Part 1): 784–789. 75 Oosterga M et al. Effects of aspirin on angiotensinconverting enzyme inhibition and left ventricular dilation one year after acute myocardial infarction. Am J Cardiol 1998; 81: 1178–1181. 76 Pancera P et al. Changes in peripheral hemodynamics and vasodilating prostaglandins after high-dose shortterm ibuprofen in chronically treated hypertensive patients. Prostaglandins Leukot Essent Fatty Acids 1996; 54: 217–222. 77 Peto R et al. Randomised trial of prophylactic daily aspirin in British male doctors. BMJ 1988; 296: 313–316. 78 Steering Committee of the Physicians’ Health Study Research Group. Final report on the aspirin component of the ongoing Physicians’ Health Study. N Engl J Med 1989; 321: 129–135. 79 Polonia J et al. Influence of non-steroidal antiinflammatory drugs on renal function and 24 h ambulatory blood pressure-reducing effects of enalapril and nifedipine gastrointestinal therapeutic system in hypertensive patients. J Hypertens 1995; 13: 925–931. 80 Polonia J, Gama G, Santos A. [Reduction of the antihypertensive effects of enalapril by indomethacin. Its independence from renal sodium retention]. Rev Port Cardiol 1996; 15: 460, 485–492. 81 Collaborative Group of the Primary Prevention Project. Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice. Lancet 2001; 357: 89–95. Journal of Human Hypertension


82 Pritchard G et al. Do trandolapril and indomethacin influence renal function and renal functional reserve in hypertensive patients? Br J Clin Pharmacol 1997; 44: 145–149. 83 Proudman SM et al. Treatment of poor-prognosis early rheumatoid arthritis. A randomized study of treatment with methotrexate, cyclosporin A, and intra-articular corticosteroids compared with sulfasalazine alone. Arthritis Rheum 2000; 43: 1809–1819. 84 Puranen J, Laakso M, Riekkinen Sr PJ, Sivenius J. Efficacy of antiplatelet treatment in hypertensive patients with TIA or stroke. J Cardiovasc Pharmacol 1998; 32: 291–294. 85 Mahaffey KW et al. Stroke in patients with acute coronary syndromes: incidence and outcomes in the platelet glycoprotein IIb/IIIa in unstable angina. Receptor suppression using integrilin therapy (PURSUIT) trial. The PURSUIT Investigators. Circulation 1999; 99: 2371–2377. 86 Saloheimo P, Juvela S, Hillbom M. Use of aspirin, epistaxis and untreated hypertension as risk factors for primary intracerebral hemorrhage in middle-aged and elderly people. Stroke 2001; 32: 399–404. 87 Schreiber TL et al. Randomized trial of thrombolysis versus heparin in unstable angina. Circulation 1992; 86: 1407–1414. 88 Sivenius J et al. Antiplatelet therapy is effective in primary prevention of myocardial infarction in patients with a previous cerebrovascular ischemic event. Arch Neurol 1993; 50: 710–713. 89 Smith SR, Coffman TM, Svetkey LP. Effect of low-dose aspirin on thromboxane production and the antihypertensive effect of captopril. J Am Soc Nephrol 1993; 4: 1133–1139.

Journal of Human Hypertension

90 Sturrock ND, Lang CC, Struthers AD. Indomethacin and cyclosporin together produce marked renal vasoconstriction in humans. J Hypertens 1994; 12: 919–924. 91 Takeuchi K et al. No adverse effect of non-steroidal anti-inflammatory drugs, sulindac and diclofenac sodium, on blood pressure control with a calcium antagonist, nifedipine, in elderly hypertensive patients. Tohoku J Exp Med 1991; 165: 201–208. 92 Thakur V, Cook ME, Wallin JD. Antihypertensive effect of the combination of fosinopril and HCTZ is resistant to interference by nonsteroidal anti-inflammatory drugs. Am J Hypertens 1999; 12(9 Part 1): 925–928. 93 Tison P et al. Treatment of hypertension with dihydropyridine calcium antagonists and aspirin. Blood Press Suppl 1994; 1: 57–60. 94 Tsuji T, Yasu T, Katayama Y, Imanishi M. Different patterns of renal prostaglandins I2 and E2 in patients with essential hypertension with low to normal or high renin activity. J Hypertens 2000; 18: 1091–1096. 95 UK-TIA Study Group. The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial: final results. J Neurol Neurosurg Psychiatry 1991; 54: 1044–1054. 96 Walter E, Kaufmann W, Oster P. Does chronic aspirin treatment increase blood pressure in man? Klin Wochenschr 1981; 59: 297–299. 97 Whelton A et al. Cyclooxygenase-2—specific inhibitors and cardiorenal function: a randomized, controlled trial of celecoxib and rofecoxib in older hypertensive osteoarthritis patients. Am J Ther 2001; 8: 85–95. 98 Celis H et al. Interaction between nonsteroidal antiinflammatory drug intake and calcium-channel blocker-based antihypertensive treatment in the Syst-Eur trial. J Hum Hypertens 2001; 15: 613–618.