Treatment of hypertension in peripheral arterial disease.

Treatment of hypertension in peripheral arterial disease (Review) Lane DA, Lip GYH

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2013, Issue 12 http://www.thecochranelibrary.com

Treatment of hypertension in peripheral arterial disease (Review) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

TABLE OF CONTENTS HEADER . . . . . . . . . . . . . . . . . . ABSTRACT . . . . . . . . . . . . . . . . . PLAIN LANGUAGE SUMMARY . . . . . . . . . BACKGROUND . . . . . . . . . . . . . . . OBJECTIVES . . . . . . . . . . . . . . . . METHODS . . . . . . . . . . . . . . . . . RESULTS . . . . . . . . . . . . . . . . . . Figure 1. . . . . . . . . . . . . . . . . Figure 2. . . . . . . . . . . . . . . . . Figure 3. . . . . . . . . . . . . . . . . Figure 4. . . . . . . . . . . . . . . . . Figure 5. . . . . . . . . . . . . . . . . Figure 6. . . . . . . . . . . . . . . . . DISCUSSION . . . . . . . . . . . . . . . . AUTHORS’ CONCLUSIONS . . . . . . . . . . ACKNOWLEDGEMENTS . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . CHARACTERISTICS OF STUDIES . . . . . . . . DATA AND ANALYSES . . . . . . . . . . . . . WHAT’S NEW . . . . . . . . . . . . . . . . HISTORY . . . . . . . . . . . . . . . . . . CONTRIBUTIONS OF AUTHORS . . . . . . . . DECLARATIONS OF INTEREST . . . . . . . . . SOURCES OF SUPPORT . . . . . . . . . . . . DIFFERENCES BETWEEN PROTOCOL AND REVIEW INDEX TERMS . . . . . . . . . . . . . . .

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[Intervention Review]

Treatment of hypertension in peripheral arterial disease Deirdre A Lane1 , Gregory YH Lip1 1 University

of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, UK

Contact address: Gregory YH Lip, University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Dudley Road, Birmingham, B18 7QH, UK. [email protected]. Editorial group: Cochrane Peripheral Vascular Diseases Group. Publication status and date: New search for studies and content updated (no change to conclusions), published in Issue 12, 2013. Review content assessed as up-to-date: 19 March 2013. Citation: Lane DA, Lip GYH. Treatment of hypertension in peripheral arterial disease. Cochrane Database of Systematic Reviews 2013, Issue 12. Art. No.: CD003075. DOI: 10.1002/14651858.CD003075.pub3. Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT Background Peripheral arterial disease (PAD) causes considerable morbidity and mortality. Hypertension is a risk factor for PAD. Treatment for hypertension must be compatible with the symptoms of PAD. Controversy regarding the effects of beta-adrenoreceptor blockade for hypertension in patients with PAD has led many physicians to stop prescribing beta-adrenoreceptor blockers. Little is known about the effects of other classes of anti-hypertensive drugs in the presence of PAD. This is the second update of a Cochrane review first published in 2003. Objectives To determine the effects of anti-hypertensive drugs in patients with both raised blood pressure and symptomatic PAD in terms of the rate of cardiovascular events and death, symptoms of claudication and critical leg ischaemia, and progression of atherosclerotic PAD as measured by ankle brachial index (ABI) changes and the need for revascularisation (reconstructive surgery or angioplasty) or amputation. Search methods For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Cochrane Peripheral Vascular Diseases Group Specialised Register (last searched March 2013) and CENTRAL (2013, Issue 2). Selection criteria Randomised controlled trials (RCTs) of at least one anti-hypertensive treatment against placebo or two anti-hypertensive medications against each other, with interventions lasting at least one month. Trials had to include patients with symptomatic PAD. Data collection and analysis Data were extracted by one author (DAL) and checked by the other (GYHL). Potentially eligible studies were excluded when the results presentation prevented adequate extraction of data and enquiries to authors did not yield raw data. Main results Eight RCTs were included with a total of 3610 PAD patients. Four studies compared a recognised class of anti-hypertensive treatment with placebo and four studies compared two anti-hypertensive treatments with each other. Studies were not pooled due to the variation of the comparisons and the outcomes presented. Overall the quality of the available evidence was unclear, primarily as a result of a lack of detail in the study reports on the randomisation and blinding procedures and incomplete outcome data. Two studies compared Treatment of hypertension in peripheral arterial disease (Review) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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angiotensin converting enzyme (ACE) inhibitors against placebo. In one study there was a significant reduction in the number of cardiovascular events in patients receiving ramipril (odds ratio (OR) 0.72, 95% confidence interval (CI) 0.58 to 0.91; n = 1725). In the second trial using perindopril (n = 52) there was a marginal increase in claudication distance but no change in ABI and a reduction in maximum walking distance. A trial comparing the calcium antagonist verapamil versus placebo in patients undergoing angioplasty (n = 96) suggested that verapamil reduced restenosis (per cent diameter stenosis (± SD) 48.0% ± 11.5 versus 69.6% ± 12.2; P < 0.01), although this was not reflected in the maintenance of a high ABI (0.76 ± 0.10 versus 0.72 ± 0.08 for verapamil versus placebo). Another study (n = 80) demonstrated no significant difference in arterial intima-media thickness (IMT) in men receiving the thiazide diuretic hydrochlorothiazide (HCTZ) compared to those receiving the alpha-adrenoreceptor blocker doxazosin (-0.12 ± 0.14 mm and -0.08 ± 0.13 mm, respectively; P = 0.66). A study (n = 36) comparing telmisartan to placebo found a significant improvement in maximum walking distance at 12 months with telmisartan (median (interquartile range (IQR)) 191 m (157 to 226) versus 103 m (76 to 164); P < 0.001) but no differences in ABI (median (IQR) 0.60 (0.60 to 0.77) versus 0.52 (0.48 to 0.67)) or arterial IMT (median (IQR) 0.08 cm (0.07 to 0.09) versus 0.09 cm (0.08 to 0.10)). Two studies compared the beta-adrenoreceptor blocker nebivolol with either the thiazide diuretic HCTZ or with metoprolol. Both studies found no significant differences in intermittent or absolute claudication distance, ABI, or all-cause mortality between the anti-hypertensives. A subgroup analysis of PAD patients (n = 2699) in a study which compared a calcium antagonist-based strategy (verapamil slow release (SR) ± trandolapril) to a beta-adrenoreceptor blocker-based strategy (atenolol ± hydrochlorothiazide) found no significant differences in the composite endpoints of death, non-fatal myocardial infarction or nonfatal stroke with or without revascularisation (OR 0.90, 95% CI 0.76 to 1.07 and OR 0.96, 95% CI 0.82 to 1.13, respectively). Authors’ conclusions Evidence on the use of various anti-hypertensive drugs in people with PAD is poor so that it is unknown whether significant benefits or risks accrue. However, lack of data specifically examining outcomes in PAD patients should not detract from the overwhelming evidence on the benefit of treating hypertension and lowering blood pressure.

PLAIN LANGUAGE SUMMARY Treatment of high blood pressure for people with peripheral arterial disease When blood pressure is consistently high it can lead to complications such as a heart attack (myocardial infarction) or stroke. Both peripheral arterial disease (PAD), a condition that affects the blood vessels (arteries) carrying the blood to the legs, arms, and stomach area, and high blood pressure (hypertension) are associated with atherosclerosis. This is hardening of the arteries which is caused by deposits of fat, cholesterol and other substances inside the blood vessels. PAD is diagnosed when the blood supply to the legs is restricted causing pain and cramping that limits walking (intermittent claudication). It is measured by the walking distance (on a treadmill) before onset of pain (claudication distance) or ankle brachial index (ABI), the ratio of the blood pressure in the arms to the blood pressure in the legs. If the blood pressure is lower in the legs compared to the arms (ABI of less than 1.0) this indicates blocked arteries in the legs (or PAD). PAD can progress to pain at rest and critical limb ischaemia (sudden lack of blood flow to a limb caused by a blood clot or fatty deposit blockage) that requires revascularisation (restoring the blood flow by opening up the blocked blood vessel) or amputation. Treatment of hypertension to reduce cardiovascular events (heart attack or stroke) and death needs careful consideration in people with PAD. Anti-hypertensive medications may worsen the PAD symptoms by further reducing blood flow and supply of oxygen to the limbs, and may have long-term effects on disease progression. The evidence from randomised controlled trials (RCTs) examining the risks and benefits of various anti-hypertensive drugs on measures of PAD is lacking. We identified eight RCTs with a total of 3610 people with symptomatic PAD where participants were randomised to receive an antihypertensive treatment for at least one month or placebo or no treatment. Four studies compared an anti-hypertensive treatment with placebo and four studies compared two anti-hypertensive treatments with each other. The studies were not combined due to the variation of comparisons and the outcomes presented. One trial with 1725 participants showed that the angiotensin converting enzyme (ACE) inhibitor ramipril was effective in reducing the number of cardiovascular events by 28% compared to placebo. In one other study using an ACE inhibitor (n = 52) the perindopril group showed a small increase in claudication distance but no change in ABI and a reduction in maximal walking distance (MWD). In patients undergoing peripheral arterial angioplasty (a procedure to open narrowed or blocked blood vessels) the results from a trial with 96 participants suggested that the calcium channel blocker verapamil reduced restenosis (new blockage of the artery) at six months. In one small study (n = 80) peripheral arterial wall thickness was similar whether men received the thiazide diuretic hydrochlorothiazide (HCTZ) or the alpha-adrenoreceptor blocker doxazosin. In another small study (n = 36) MWD was improved at 12 months in the angiotensin-II receptor antagonist telmisartan group compared to the placebo group but there were no significant differences in ABI or arterial wall thickness. Another study (n = 163) found no Treatment of hypertension in peripheral arterial disease (Review) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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significant differences in intermittent or absolute claudication distance, ABI, all-cause mortality or non-fatal cardiovascular events after 24 weeks of treatment in the beta-adrenoreceptor blocker nebivolol group and the HCTZ group. A study comparing two betaadrenoreceptor blockers, nebivolol and metoprolol, found no clear differences in intermittent or absolute claudication distance, ABI, all-cause mortality or revascularisation after 36 weeks of treatment. A subgroup analysis of PAD patients (n = 2699) in the final study revealed no significant differences in the combined endpoints of death, non-fatal myocardial infarction or non-fatal stroke with or without revascularisation between the calcium antagonist-based strategy (verapamil slow release (SR) with or without trandolapril) compared to the beta-adrenoreceptor blocker strategy (atenolol with or without HCTZ). The evidence on the use of various anti-hypertensive drugs in people with PAD is poor so that it is not known whether significant benefits or risks accrue. However, lack of data specifically examining outcomes in hypertensive PAD patients should not detract from the overwhelming evidence on the benefit of treating hypertension and lowering blood pressure.

BACKGROUND Description of the condition Peripheral arterial disease (PAD) is a condition that affects the blood vessels (arteries) carrying the blood to the legs, arms, and stomach area. PAD occurs when these arteries start to narrow because of a build-up of fatty deposits inside the blood vessels. PAD mainly affects the arteries in the legs. It can cause discomfort or pain in the lower legs when walking because the narrowing in the blood vessels means that less oxygen-rich blood reaches the legs. This discomfort or pain is called intermittent claudication. Not everyone has these symptoms. PAD is the third leading cause of morbidity from atherosclerotic disease (disease of the arteries caused by the build-up of fatty deposits on the inner lining of the blood vessels) after coronary heart disease and stroke (Fowkes 2013). PAD is the cause of a large number of hospital admissions each year. In the United States of America, 9.6% of cardiovascular events are due to PAD, resulting in 63,000 annual hospital admissions (Kannel 1996). In addition, PAD is associated with significant morbidity and mortality (Criqui 1992; Clement 2007; Fowkes 2013). Patients with PAD, with and without intermittent claudication, have almost three times the risk of dying or having a major cardiovascular event (stroke or heart attack) compared to people without PAD (Pande 2011; Fowkes 2013). Although the risk of non-fatal cardiovascular events (morbidity) among patients with intermittent claudication is reported to be approximately five to 10 in every 100 patients (Dormandy 2000) the risk of death is much higher. For example, the Framingham study showed that two out of every five patients with intermittent claudication died within 10 years of being diagnosed with PAD (Murabito 2005); this high adverse outcome is also reported in several other studies (Reunanen 1982; Bowlin 1997; Dormandy 2000; Feringa 2006) and the risk is similar whether the patient is symptomatic or not (Criqui 1992).

Hypertension is the name given to high blood pressure that is consistently at such a level that it can cause disease or lead to complications (for example myocardial infarction (MI) (known as a heart attack) or stroke). Hypertension is a common and important risk factor for all vascular disorders including PAD (Kannel 1974; Fowkes 1992; Clement 2007). At presentation, between 2% and 5% of hypertensive patients have intermittent claudication, and this prevalence increases with age. Similarly, 35% to 55% of patients with PAD at presentation also have hypertension (Johnston 1988; Novo 1992; Binaghi 1994; Violi 1996; Cheng 1999; Hirsch 2001; Clement 2007; Singer 2008). Patients who suffer from either hypertension or PAD have a high risk of MI and stroke and when hypertension and PAD are both present the risk is greatly increased (Makin 2001; Clement 2007; Singer 2008). Hypertension contributes to the pathogenesis (progression of disease) of atherosclerosis (the basic pathological process underlying PAD) (Simon 1986; Bauwens 1989; McGill 1998). Indeed, both hypertension and PAD are associated with abnormal levels of lipid and coagulation factors in the blood (Makin 2002).

Description of the intervention Given the co-existence of PAD and hypertension, the overlap in risk factors between the two conditions, the increased risk of nonfatal cardiovascular events in PAD, and the greater risk of death (Criqui 1992; Murabito 2005; Clement 2007; Fowkes 2013) treatment guidelines highlight the importance of reducing the patient’s overall cardiovascular risk as well as targeting the individual risk factors (Clement 2007; ESH 2013). Treatment of hypertension in patients with symptoms of PAD is an obvious therapeutic target but this needs careful consideration because of the possibility that the anti-hypertensive medication will cause secondary effects and alter the process(es) causing PAD. While beta-adrenoreceptor blockers (which block the action of noradrenaline and adrenaline


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on the heart and thus help to reduce blood pressure) are recommended for use in MI to increase survival (Hjalmarson 1997), there has been some concern that they may worsen the symptoms of intermittent claudication for people with PAD although several studies have shown that there is no evidence to support this (Bogaert 1983; Hiatt 1985; Radack 1991). In addition to betaadrenoreceptor blockers, there are other classes of anti-hypertensives that are commonly used to reduce blood pressure including diuretics, calcium channel blockers (CCBs), angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and alpha-adrenoreceptor blockers.

How the intervention might work The mechanism thought to cause the worsening of PAD symptoms with beta-adrenoreceptor blockers is peripheral vasoconstriction (narrowing of peripheral blood vessels) leading to further ischaemia in an already ischaemic limb (reducing blood flow to limbs that already have a poor oxygen supply). There is only scant evidence for this with studies showing either no change in walking distance when one beta-adrenoreceptor blocker is used (Solomon 1991) or a deterioration (Schweizer 1996), particularly when two beta-adrenoreceptor blockers are combined (Solomon 1991). Some beta-adrenoreceptor blockers (for example nebivolol or carvedilol) have ’intrinsic sympathomimetic activity’ (ISA) that mimics the effects of the sympathetic nervous system causing the blood vessels away from the heart (for example in the feet) to open up (vasodilation) thus allowing greater blood flow. This might be useful for patients with impaired blood flow to the lower extremities (the legs). If too much sodium is retained by the body, this can lead to fluid overload and increases the blood pressure. Diuretics work by increasing the flow of urine thereby removing sodium and chloride (and in turn water) from the body and can help to lower blood pressure. Control of blood pressure can help reduce the risk of cardiovascular events which are common in PAD patients. Dihydropyridine calcium channel blockers (for example, amlodipine, felodipine, nifedipine) cause vasodilation thereby helping to lower blood pressure. CCBs such as verapamil and diltiazem also vasodilate blood vessels but they can reduce cardiac output by lowering the heart rate and impair cardiac systolic function. As a result, the ’cardioselective’ CCBs should not be used in patients with concomitant heart failure. ACE inhibitors inhibit the conversion of the inactive form of the hormone angiotensin to the active form. The active form raises blood pressure, thus blocking its formation with ACE inhibitors helps to reduce blood pressure. There is some evidence that ACE inhibitors increase peripheral perfusion (blood flow) and claudication distance (walking distance before onset of pain in people who have this symptom, known as claudicants) in normotensive PAD patients (Breckenridge 1992; Ahimastos 2006) although concerns about exacerbating renal artery stenosis (blockage) arise (Makin

2001). These agents are also increasingly recognised for their cardioprotective effects (HOPE 1996). Angiotensin receptor blockers (ARBs) have very similar properties to ACE inhibitors. ARBs selectively block the receptor for angiotensin-II to inhibit vasoconstriction (narrowing of the blood vessels), secretion of aldosterone, and sodium and water retention, thereby helping to lower blood pressure. Cardioselective beta-adrenoreceptor blockers, CCBs, ACE inhibitors and ARBs may potentially help to reduce leg pain by increasing the blood flow to the legs thereby increasing pain-free walking distance. In addition, these drugs have been shown to reduce blood pressure and the risk of cardiovascular events in hypertensive populations and in those with coronary heart disease (ABCD 2003; HOPE 2004; INVEST 2006; VALUE 2006) some of which have included patients with concomitant PAD. Long-acting alpha-adrenoreceptor blockers such as doxazosin also have vasodilating properties (increasing the blood flow) and are recommended as fourth line drugs, in addition to other anti-hypertensive drugs, in people with resistant hypertension (ESH 2013).

Why it is important to do this review Current guidelines for treating hypertension recommend an individualised approach using anti-hypertensive agents (ESH 2013). There is scant evidence from randomised controlled trials of the benefit or harm of one class of anti-hypertensive medication over another in PAD patients and subsequently there are no specific national guidelines on the choice of blood pressure medication in patients with PAD. However, a consensus document for the management of PAD (TASC-II 2007) highlights that controlling a patient’s total cardiovascular risk is paramount in such patients. Identification of individual cardiovascular risks, of which hypertension is prevalent, is the first step in the recommendations with subsequent optimal management of each risk factor. Addressing overall cardiovascular risk necessitates polypharmacy and a regimen that includes anti-platelet agents, statins and an ACE inhibitor (unless contraindicated) plus lifestyle modification (smoking cessation, reduction of salt intake, weight control and exercise) (Clement 2007; TASC-II 2007). Co-morbidities need to be considered when making decisions about treatment (Clement 2007; Singer 2008) as these may indicate that one anti-hypertensive is preferable to another in a particular patient, for example use of a beta-adrenoreceptor blocker or ACE inhibitor following an acute coronary syndrome or avoidance of the CCB verapamil or diltiazem in those with concomitant heart failure. Anti-hypertensive drugs have been used for many years in the treatment of hypertension although little is known of their effect in PAD. Therefore, before prescribing anti-hypertensive medication for people suffering with PAD, the short-term effects on symptoms and the longerterm effects on disease progression and cardiovascular outcomes should be considered.


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OBJECTIVES To conduct a systematic review to determine the effects of antihypertensive drugs in patients with both raised blood pressure and symptomatic peripheral arterial disease (PAD) in terms of:

and include patients with symptomatic PAD. The intervention in each group had to last for at least one month.

Types of outcome measures

• rate of cardiovascular events and death; • symptoms of claudication and critical leg ischaemia; • progression of atherosclerotic PAD as measured by ankle brachial index changes and the need for revascularisation (reconstructive surgery or angioplasty) or amputation.

Primary outcomes

1. All-cause mortality 2. Cardiovascular deaths (stroke, myocardial infarction (MI), pulmonary embolism, peripheral arterial embolism) 3. Non-fatal cardiovascular events (stroke, MI, pulmonary embolism, peripheral arterial embolism)

METHODS Secondary outcomes

Criteria for considering studies for this review

Types of studies Randomised controlled trials (RCTs) comparing at least one recognised class of anti-hypertensive treatment against placebo or two anti-hypertensive medications against each other and including patients with symptomatic PAD as either the study population or a subgroup. The intervention must have been for at least one month in each group. Studies were excluded when the trial design was adequate but the published data were inadequate for the purposes of the review, or if all attempts to contact the authors to obtain further data were unsuccessful. Cross-over trials were excluded as they would not be suitable for measures of disease severity and progression in view of the erroneous assumption that any effects are fully reversible after each treatment.

Types of participants Patients with PAD and hypertension. For the purposes of this review PAD was restricted to the effects of PAD thus including those patients with intermittent claudication (IC) and critical limb ischaemia (CLI) (as defined by ischaemic rest pain) and excluding patients with aortic aneurysm, carotid disease, thrombophlebitis, and vasospasm. Hypertension was defined as elevated blood pressure (based on the current definition of hypertension at the time of recruitment) or was assumed in patients receiving anti-hypertensive medication.

Types of interventions To be eligible for inclusion, trials had to include an intervention of at least one recognised class of anti-hypertensive treatment against placebo or two anti-hypertensive medications against each other

1. Measurements of disease severity, including claudication distance on a treadmill and ankle-brachial index (ABI) 2. Measurements of disease progression (e.g. ABI and arterial intima-media thickness (IMT)) 3. Need for revascularisation and other vascular interventions (e.g. bypass surgery, angioplasty, amputation)

Search methods for identification of studies There were no language restrictions and relevant papers that were in languages other than English were translated.

Electronic searches For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator (TSC) searched the Cochrane Peripheral Vascular Diseases Group Specialised Register (last searched March 2013) and the Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 2), part of The Cochrane Library (www.thecochranelibrary.com). See Appendix 1 for details of the search strategy used to search CENTRAL. The Specialised Register is maintained by the TSC and is constructed from weekly electronic searches of MEDLINE, EMBASE, CINAHL and AMED, and through handsearching relevant journals. The full list of the databases, journals and conference proceedings which have been searched, as well as the search strategies used, are described in the Specialised Register section of the Cochrane Peripheral Vascular Diseases Group module in The Cochrane Library (www.thecochranelibrary.com). For the original review, the authors searched the National Health Service Database of Abstracts of Reviews of Effectiveness (DARE) (last searched August 2002) to identify potentially eligible studies and review articles.


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Searching other resources Reference lists of relevant articles were screened.

Data collection and analysis

Selection of studies Both review authors (DAL, GYHL) independently selected trials for inclusion in the review. Disagreements were resolved by discussion.

Data extraction and management DAL extracted the data, which were checked by GYHL. The data extracted included information relating to the complexities of the topic area, such as patient characteristics and concomitant treatments, as well as data relating to study eligibility, quality and outcomes. Disagreements between review authors on data extraction were resolved by discussion.

drug containers of identical appearance; sequentially numbered opaque, sealed envelopes. High risk of bias, if the participants or investigators enrolling participants could possibly foresee assignments and thus introduce selection bias, such as allocation based on using an open random allocation schedule (for example a list of random numbers); assignment envelopes used without appropriate safeguards (for example if envelopes were unsealed or non-opaque, or not sequentially numbered); alternation or rotation; date of birth; case record number. Unclear risk of bias, if there was insufficient information to permit judgement of low or high risk of bias. This was usually the case if the method of concealment was not described or not described in sufficient detail to allow a definite judgement (for example if the use of assignment envelopes was described but it remained unclear whether envelopes were sequentially numbered, opaque and sealed). Where the method of allocation was unclear, we planned to contact study authors for them to provide further details.

Blinding Assessment of risk of bias in included studies For the updated review, risk of bias was assessed independently by the review authors using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We assessed the domains listed below. There were three possible judgements: ’low’ risk of bias, ’high’ risk of bias, and if insufficient detail was reported the judgement on risk of bias was judged to be ’unclear’. We assessed the new studies included in the updated review and we reassessed the studies already included in the previous versions of the review using these criteria.

Sequence generation Low risk of bias, if the allocation sequence was generated using techniques such as a random number table; a computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice. High risk of bias, if the allocation sequence was generated using techniques such as odd or even date of birth; date (or day) of admission; hospital or clinic record number. Unclear risk of bias, if there was insufficient information about the sequence generation process to permit judgement.

Allocation concealment Low risk of bias, if the allocation concealment used methods such as central allocation (including telephone, web-based, and pharmacy-controlled randomisation); sequentially numbered

Low risk of bias, if there was no blinding but the review authors judged that the outcome and the outcome measurement were not likely to be influenced by lack of blinding; blinding of participants and key study personnel was ensured and it was unlikely that the blinding could have been broken; either participants or some key study personnel were not blinded but outcome assessment was blinded and the non-blinding of others was unlikely to introduce bias. High risk of bias, if there was no blinding or incomplete blinding and the outcome or outcome measurement was likely to be influenced by lack of blinding; blinding of key study participants and personnel was attempted but it was likely that the blinding could have been broken; either participants or some key study personnel were not blinded and the non-blinding of others was likely to introduce bias. Unclear risk of bias, if there was insufficient information to permit judgement of low or high risk of bias or the study did not address this outcome (for example where the blinding was described only as double-blind without any other details).

Incomplete data assessment (loss of participants, for example with withdrawals, dropouts, protocol deviations) Low risk of bias, if there were no missing outcome data; reasons for missing outcome data were unlikely to be related to the true outcome; missing outcome data were balanced in numbers across intervention groups, with similar reasons for missing data across groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk was not enough to


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have a clinically relevant impact on the intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardised difference in means) among missing outcomes was not enough to have a clinically relevant impact on observed effect size; missing data were imputed using appropriate methods. High risk of bias, if the reasons for missing outcome data were likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk was enough to introduce clinically relevant bias in the intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardised difference in means) among missing outcomes was enough to introduce clinically relevant bias in observed effect size; ’as-treated’ analysis done with substantial departure of the intervention received from that assigned at randomisation; potentially inappropriate application of simple imputation. Unclear risk of bias, if there was insufficient reporting of attrition or exclusions to permit judgement of low or high risk of bias (for example numbers randomised were not stated, no reasons for missing data were provided); or the study did not address this.

the specific study design used; stopped early due to some datadependent process (including a formal stopping rule); had extreme baseline imbalance; had been claimed to be fraudulent; had some other problem). Unclear risk of bias, if there was either insufficient information to assess whether an important risk of bias existed or if there was insufficient rationale or evidence that an identified problem would introduce bias.

Measures of treatment effect Statistical analyses were undertaken as follows. For continuous variables (for example the change in IC distance between baseline and follow-up) where the data were presented as mean ± standard deviation (SD) the weighted mean difference with 95% confidence interval (CI) was used. Where continuous variables were presented as median (95% CI) the original data from the study were reported as ’other data’. As a summary measure of effectiveness (for example reduction in all-cause mortality) the odds ratio (OR) with 95% CI was calculated for dichotomous variables.

Unit of analysis issues Selective outcome reporting Low risk of bias, if the study protocol was available and all of the study’s pre-specified (primary and secondary) outcomes that were of interest in the review were reported in the pre-specified way; the study protocol was not available but it was clear that the published reports included all expected outcomes, including those that were pre-specified. High risk of bias, if not all of the study’s pre-specified primary outcomes were reported; one or more primary outcomes were reported using measurements, analysis methods or subsets of the data (for example subscales) that were not pre-specified; one or more reported primary outcomes were not pre-specified (unless clear justification for their reporting was provided, such as an unexpected adverse effect); one or more outcomes of interest in the review were reported incompletely so that they could not be entered in a meta-analysis; the study report failed to include results for a key outcome that would be expected to have been reported for such a study. Unclear risk of bias, if there was insufficient information to permit judgement of low or high risk of bias.

Other sources of bias Low risk of bias, if the study appeared to be free of other sources of bias. High risk of bias, if there was at least one important risk of bias (for example the study had a potential source of bias related to

In each of the included studies, participants were individually randomised to one of two intervention groups and the analyses were conducted with each patient as the individual unit of analysis, that is with a single measurement for each outcome collected for each patient and analysed. There were no cross-over trials, cluster-randomised trials or any other non-standard designs.

Dealing with missing data For unpublished studies, or where data were incomplete in published papers, attempts were made to contact authors or researchers to obtain further details. For the original review, no reply was received from six authors who were approached (Bostrom 1986; Novo 1986; Rouffy 1989; Solomon 1991; Sutton-Tyrell 1995; Casiglia 1997). A reply was received from one (Bogaert 1983) saying that the original data were no longer available. For the 2009 review update, five large RCTs of anti-hypertensive treatment in hypertensive patients where there were significant numbers of patients with PAD were also identified (LIFE 2002; INVEST 2003; ASCOT 2005; VALUE 2006; ONTARGET 2008). The steering committees for each of these trials were contacted to obtain the raw data for those hypertensive patients with PAD. However, these committees were waiting for publication of the subgroup data before making the data available to us. For this updated review (2013), a subgroup analysis of the INVEST 2003 trial participants with hypertension and PAD was identified (Bavry 2010a) and the data were included. Data on the subgroup of hypertensive patients with PAD from the remaining four large RCTs were still unavailable for this updated review (LIFE 2002; ASCOT 2005; VALUE


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2006; ONTARGET 2008). Should the data become available, these trials will be included in the next update of this review. Assessment of heterogeneity We were not able to perform any meta-analysis as included studies compared different types of anti-hypertensive drugs, to each other or to placebo, and outcomes measured were not common among all studies. However, if meta-analysis had been possible, we would have applied tests of heterogeneity between trials, as appropriate, using the I2 statistic. Where high levels of heterogeneity among the trials (I2 > 50%) were identified, we would have explored it using subgroup analysis and by performing sensitivity analysis. We would have used a random-effects model meta-analysis for an overall summary, if this had been considered appropriate. Assessment of reporting biases There were not enough studies in this review to test for reporting bias, thus the review is discussed as a narrative review. Data synthesis It was not possible to perform any meta-analysis as included studies compared different types of anti-hypertensive drugs, to each other or to placebo, and outcomes were not common among all studies. Results of the individual studies were combined into a narrative review. Subgroup analysis and investigation of heterogeneity There were insufficient studies to carry out subgroup analyses. Future revisions of the review may examine different medications within one class of drug (for example atenolol, metoprolol, nebivolol) where the comparator is identical, the duration of the treatment, or treatment effects in men versus women. This will be dependent upon the availability of such data in the included study reports. Sensitivity analysis There were insufficient studies to carry out sensitivity analyses. However, future revisions of the review may employ sensitivity analyses to examine factors that may lead to differences between the results of individual trials including poor quality versus good quality trials.

RESULTS

Description of studies

Results of the search For this 2013 update, following screening of titles and abstracts full texts of 77 references to 57 trials were obtained and considered. Four new studies were included in this update and seven new studies were excluded.

Included studies See the table Characteristics of included studies. In total, eight trials were finally included in this review (Overlack 1994; Schweizer 1998; DAPHNE 2002; INVEST 2003; HOPE 2004; Zankl 2010; Diehm 2011; NORMA 2011). A subgroup analysis of the PAD patients enrolled in the INVEST 2003 trial was published in 2010 (Bavry 2010a), therefore this study was moved from the excluded studies to the included studies for this update.

Interventions

Four studies compared anti-hypertensive therapy against placebo (Overlack 1994; Schweizer 1998; HOPE 2004; Zankl 2010), with two of these studies comparing angiotensin converting enzyme (ACE) inhibitors with placebo (Overlack 1994; HOPE 2004), another (Schweizer 1998) comparing a calcium channel blocker (CCB) with placebo, and one (Zankl 2010) comparing an angiotensin-II receptor antagonist with placebo. Three studies compared two anti-hypertensive agents against each other (DAPHNE 2002; Diehm 2011; NORMA 2011); one study compared a thiazide diuretic with an alpha-adrenoreceptor blocking agent (DAPHNE 2002), one a beta-adrenoreceptor blocking agent with a thiazide diuretic (Diehm 2011) and another compared two beta-adrenoreceptor blocking agents against each other (NORMA 2011). Another study, a subgroup analysis of the INVEST 2003 trial (Bavry 2010a), compared a calcium antagonist-based strategy with a beta-adrenoreceptor blocking strategy.

Description of PAD

The description of how PAD was diagnosed differed between the included studies. In the INVEST (INternational VErapamil-SR/ Trandolapril) study (INVEST 2003), PAD was defined as a documented history of peripheral vascular disease on the baseline form. Schweizer et al (Schweizer 1998) used the Fontaine Stage IIb classification (Fontaine 1954), that is, a pain-free walking distance of less than 200 m without ischaemic rest pain or trophic changes (changes in skin and muscle related to chronic ischaemia, although how this was quantified was not explained); in addition to arterial angiography and colour-coded duplex ultrasound occlusion (diameter ≤ 5 cm) or subtotal stenoses in the distal superficial femoral artery that were present for > six months. Overlack et al (Overlack 1994) included patients with a history of IC for ≥


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six months and Fontaine Stage IIb disease who had a proven occlusion on angiography. Zankl et al (Zankl 2010) included patients with documented PAD and at least Stage Fontaine IIa. The NORMA (Nebivolol or Metoprolol in Arterial Occlusive Disease) trial (NORMA 2011) defined PAD as stable IC (Fontaine Stage II) for ≥ six months and an ABI < 0.9 (measured as the ratio of systolic blood pressure in the ankle and arm). The HOPE trial (HOPE 2004) defined PAD as either a history of IC with an ABI < 0.9 (measured by manual palpation of the foot pulse and not ultrasound doppler) or previous vascular intervention or limb amputation for PAD. Diehm et al (Diehm 2011) included patients with one or more of the following: a history of typical IC for at ≥ six months; actual proven PAD by objective means such as haemodynamics and non-invasive imaging or angiography; history of previous vascular intervention; or ABI of the worse leg < 0.9. In the DAPHNE (Doxazosin Atherosclerosis Progression in Hypertension in the NEtherlands) study (DAPHNE 2002) PAD was defined as IC or peripheral vascular surgery because of atherosclerosis.

Definition of hypertension

The studies used a variety of different criteria to define hypertension. Schweizer (Schweizer 1998) and Overlack (Overlack 1994) included patients with mild essential hypertension, which was quantified in one study (Overlack 1994) as a sitting diastolic blood pressure of 95 to 104 mmHg on three different occasions. The DAPHNE study defined hypertension on the basis of diastolic blood pressure alone, 95 to 115 mmHg in two out of three supine readings (DAPHNE 2002). The HOPE study defined hypertension as blood pressure > 160/90 mmHg or on the basis that people were on anti-hypertensive treatment (HOPE 2004). Zankl et al (Zankl 2010) included patients with arterial hypertension which was not defined but those with uncontrolled hypertension (systolic blood pressure ≥ 170 mmHg and diastolic blood pressure ≥ 95 mmHg or both) were excluded. The NORMA study (NORMA 2011) included patients with stage I arterial hypertension (systolic blood pressure (SBP) 140 to 159 mmHg and diastolic blood pressure (DBP) 90 to 99 mmHg) or a previous diagnosis of stage I arterial hypertension who were under current treatment. At the time of inclusion, SBP had to be > 100 mmHg and < 160 mmHg, with DBP < 100 mmHg (NORMA 2011). Diehm et al (Diehm 2011) included patients with a SBP between 140 and 179 mmHg and a DBP 90 to 109 mmHg with or without treatment with antihypertensive drugs at screening. After a four-week run-in period, the second eligibility criterion for hypertension was a SBP > 130 mmHg and DBP pressure > 85 mmHg (NORMA 2011). The INVEST study (INVEST 2003) included patients with essential hypertension defined as SBP > 140 mmHg and DBP > 90 mmHg (if diabetes or renal impairment was present hypertension was defined as SBP > 130 mmHg and DBP > 85 mmHg) requiring treatment.

Excluded studies See the table Characteristics of excluded studies. Fifty-nine studies were excluded for the following reasons. 1. Ten studies were excluded because the treatment period was shorter than the month specified in the review protocol (Reichert 1975; Smith 1982; Lepantalo 1984; Hiatt 1985; Lepantalo 1985a; Klieber 1986; Bernardi 1988; Natali 1989; Kalus 1995; Liu 1997). 2. Seven studies were eligible for inclusion but the data presentation in the papers was inadequate and attempts to obtain the specific data failed. For six of these trials the authors were contacted but did not respond (Bostrom 1986; Novo 1986; Rouffy 1989; Solomon 1991; Sutton-Tyrell 1995; Casiglia 1997). For one study (Bogaert 1983) the author was successfully contacted but the data were not available as the study had been conducted several years ago. 3. Nine studies did not include patients with PAD (Lepantalo 1983; Panzner 1992; Weibull 1992; Stumpe 1993; Leeman 1995; Stumpe 1995; OPERA 2002; POISE 2008; Takeda 2010). 4. Six studies were not RCTs (Ingram 1982; Winterfeld 1984; Lepantalo 1985b; Novo 1985; Coto 1991; Van de Ven 1994). 5. Eight studies did not use anti-hypertensive medication (Larsen 1969; Domschky 1977; Jageneau 1977; Nelson 1978; Staessen 1978; Coto 1989; Branchereau 1995; Lievre 1996). 6. Two studies were excluded because none of the outcome measures matched those predefined for this review (Siniscalchi 1993; Brown 1998). 7. Four studies were excluded because the patients were not hypertensive at the outset of the trial, or hypertensive patients were excluded (Spence 1993; Laurent 1994; Schweizer 1996; Ahimastos 2006). 8. Two trials (Svendsen 1986; Roberts 1987) were cross-over trials with a washout period at the start of the trial; the postintervention data from both or all phases were presented lumped together and not separately. Another trial (Roberts 1992) was a cross-over trial with no washout phase between treatments; the data from both phases were presented lumped together. 9. Another trial compared captopril against ticlopidine but did not compare captopril against placebo (Novo 1996). In addition, this trial (Novo 1996) only used ABI to confirm diagnosis although the exact value used was not mentioned. 10. One study involved open-label administration of vasodilating agents to control blood pressure, if necessary, thus making the results of dubious value (Diehm 1993). 11. One publication (Mann 1998) was excluded because it was a protocol for an RCT with no data. Another study was excluded as it was a comment on the results of the ONTARGET trial and did not present any data (Liakishev 2008). One publication was excluded because it was only published as an abstract although the full abstract was not available (Gastmann 1987). 12. The data for PAD patients were not available from five RCTs (LIFE 2002; ABCD 2003; ASCOT 2005; VALUE 2006;


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ONTARGET 2008).

Risk of bias in included studies See the table Characteristics of included studies. For the updated review, risk of bias was assessed independently by two review authors using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). The results are displayed in Figure 1 and Figure 2. Figure 1. Methodological quality graph: review authors’ judgements about each methodological quality item presented as percentages across all included studies.


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Figure 2. Methodological quality summary: review authors’ judgements about each methodological quality item for each included study.


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Allocation Two (HOPE 2004; Diehm 2011) of the included studies provided information about adequate random sequence generation and allocation concealment. Patients were randomised using a central telephone service in the HOPE study (HOPE 2004), and Diehm used a computer-generated randomisation list (Diehm 2011). There was a low risk of bias in allocation concealment in both these studies (HOPE 2004; Diehm 2011) as treatment was double-blind. In the subgroup analysis of the INVEST study (INVEST 2003) there was a low risk of bias in random sequence generation because patients were randomised using an electronic system available via the Internet. However, allocation concealment was unclear because, although the investigator was informed electronically of treatment allocation, the treatment was open label. In five of the included studies (Overlack 1994; Schweizer 1998; DAPHNE 2002; Zankl 2010; NORMA 2011) patients were randomised to the treatment arms but it was unclear if there was any selection bias because no further description of the random sequence generation or allocation concealment process was provided.

Blinding The HOPE study (HOPE 2004) demonstrated a low risk of performance bias and detection bias because the trial was doubleblind and the outcome of cardiovascular events was classified by a committee of two clinicians blinded to treatment allocation who reviewed clinical records of all cardiovascular events reported by recruiting centres to determine whether they met the endpoint criteria. In one study (Diehm 2011) the risk of performance bias and detection bias for patients and physicians was low because both were blinded to treatment allocation and the nebivolol and hydrochlorothiazide (HCTZ) tablets were manufactured to be identical in size and appearance. However, no detail was given on the blinding of the outcome assessors (Diehm 2011). In four studies (Overlack 1994; Schweizer 1998; DAPHNE 2002; NORMA 2011) both the patients and the physicians were blinded to treatment but no further details were given on patient or physician blinding resulting in an unclear risk of bias. In addition, no details were given on the blinding of outcome assessments in three of these studies (Overlack 1994; DAPHNE 2002; NORMA 2011). In the study by Schweizer (Schweizer1998) two of the three outcomes (assessed by colour-coded duplex scan) were reviewed by two independent experts who were unaware of which group the participant was allocated to. In another study (Zankl 2010) the risk of performance bias and detection bias was unclear as the trial design was single-blind and, although the physician was not aware of treatment allocation, no information was available on the blinding process of the patients, physicians or outcome assessors.

The INVEST study (INVEST 2003) had a high risk of performance bias and detection bias in terms of the patients and physicians as INVEST was an open-label trial. Physicians could downtitrate the initial dose of verapamil or HCTZ monotherapy or uptitrate medication in a stepped fashion and the final step of treatment titration allowed the physician to add in any non-study antihypertensive (except beta-adrenoreceptor blockers for calcium antagonist-based strategy patients and calcium antagonists for betaadrenoreceptor blocker strategy patients) at their discretion to control blood pressure. However, outcomes were adjudicated by a blinded events committee resulting in a low risk of bias in outcome assessment (INVEST 2003).

Incomplete outcome data The attrition rate varied from 2.5% (INVEST 2003) to 31% (DAPHNE 2002). One study had a low risk of attrition bias as only three patients (verapamil n = 1, placebo n = 2) who were randomised to treatment were not included in the outcome analyses (Schweizer 1998). Another study (DAPHNE 2002) had a high risk of attrition bias as 25% of patients dropped out overall but the attrition rate was higher with HCTZ (30.8%) than doxazosin (19.5%). In the other seven studies (Overlack 1994; DAPHNE 2002; INVEST 2003; HOPE 2004; Zankl 2010; Diehm 2011; NORMA 2011) the risk of attrition bias was unclear. In the subgroup analysis of INVEST (INVEST 2003) 2.5% of patients with concomitant PAD were lost to follow-up and no further detail was available on these participants. In the study by Diehm, 14 (9.2%) patients who were randomised were not included in the intention-to-treat (ITT) analysis and no detail was given on these patients (Diehm 2011). In the NORMA trial (NORMA 2011) 19 (14.8%) patients dropped out, approximately twice as many in the nebivolol group (n = 13) compared to the metoprolol group (n = 6). In the HOPE study (HOPE 2004) the permanent discontinuation rate was around 30% but it was similar between the treatment arms (ramipril 28.9% versus placebo 27.3%) and the data were analysed on an ITT basis. In the Overlack study (Overlack 1994) the overall dropout rate was 3.2% and 1.7% in the treatment and placebo groups, respectively, but the actual number of PAD patients with follow-up data was not clear. In the Zankl study (Zankl 2010) the attrition rate was 10% (n = 4) due to premature discontinuation of the study medication because of non-adherence but no detail was given on which drug they were randomised to.

Selective reporting


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The HOPE study (HOPE 2004) had a low risk of reporting bias as data were presented on all the pre-specified outcome measures listed in the methods by the trialists and analyses were ITT. Four studies (Overlack 1994; Schweizer 1998; INVEST 2003; NORMA 2011) had a high risk of reporting bias. Overlack did not report all the data collected for the various subgroups, just the most disease-specific or relevant outcomes (Overlack 1994). Two studies (Schweizer 1998; INVEST 2003) did not report on all outcomes. Schweizer did not report distance to claudication after treatment (Schweizer 1998) and the subgroup analysis of the PAD patients from the INVEST study (INVEST 2003) only reported the two composite endpoints whereas the INVEST protocol and main results papers stated that the individual components of the composite endpoints were also outcomes. In the NORMA study (NORMA 2011) the data analysis section stated that analyses were performed for two populations: the safety population (those who received ≥ one dose of double-blind medication) and an endpoint population (all patients for whom the endpoint variables were available). However, only the endpoint analyses on 109 (85.2%) patients were reported. Despite providing data on all endpoints, three studies (DAPHNE 2002; Zankl 2010; Diehm 2011) had an unclear risk of reporting bias as outcome data were not available on those who dropped out. Other potential sources of bias

66.5% of patients screened. In the NORMA study (NORMA 2011) only post-menopausal women were eligible to be included and there was a borderline significant difference in the number of men in the two treatment groups, with a trend towards more men in the nebivolol group.

Measurement bias

One study (DAPHNE 2002) had an unclear risk of bias relating to measurement. In the DAPHNE study (DAPHNE 2002), measurements of the IMT from the carotid and femoral arteries were “quality controlled by repeated measurement procedure”, but intra- and inter-observer variability was not reported.

Effects of interventions We did not conduct a meta-analysis because the eight studies compared different types of anti-hypertensive drugs to each other or to placebo and outcomes were not common among all studies. Therefore, we have presented the data and discussed results separately for the eight included studies (Overlack 1994; Schweizer 1998; DAPHNE 2002; INVEST 2003; HOPE 2004; Zankl 2010; Diehm 2011; NORMA 2011). In future updates of the review, as new studies emerge and previously unavailable data from five identified studies (LIFE 2002; ABCD 2003; ASCOT 2005; VALUE 2006; ONTARGET 2008) become available, it may be possible to add further comparisons and, where appropriate, combine findings in a meta-analysis.

Inclusion bias

Four studies (INVEST 2003; Zankl 2010; Diehm 2011; NORMA 2011) had a potential risk of bias relating to patient inclusion. In the subgroup analysis of PAD patients enrolled in INVEST (INVEST 2003), patients were not randomised to treatment based on the presence of PAD, however there were no significant baseline differences between PAD patients randomised to the two treatment arms. In addition, the definition of PAD employed in INVEST was a documented history of PAD at baseline and no detailed information regarding the diagnosis of PAD was available (INVEST 2003). Zankl (Zankl 2010) stated that there were baseline differences between the two groups despite randomisation (not reported) but analysis of covariance (ANCOVA) was performed, which found no confounding effects of differences in baseline values on treatment. Diehm (Diehm 2011) only randomised

Comparison 1 - ACE inhibitors versus placebo Two trials compared the effects of the ACE inhibitors and placebo (Overlack 1994; HOPE 2004). In the HOPE study (HOPE 2004), when the 836 patients receiving ramipril were compared to the 889 patients receiving placebo there was a significant reduction in the number of cardiovascular events (combined endpoint of cardiovascular death, non-fatal MI and non-fatal stroke) with ramipril (OR 0.72, 95% CI 0.58 to 0.91) (HOPE 2004) (Figure 3). In the other study (Overlack 1994), when the 26 patients treated with perindopril were compared to the 28 patients on placebo there was a marginal increase in claudication distance (MD 8.0 m, 95% CI 0.49 to 15.51) and a reduction in maximal walking distance (MD -46.00 m, 95 % CI -69.74 to -22.26) but no change in ABI (MD 0, 95% CI -0.03 to 0.03) (Figure 4).


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Figure 3. Forest plot of comparison: 1 ACE inhibitors versus placebo, outcome: 1.1 Cardiovascular events.

Figure 4. Forest plot of comparison: 1 ACE inhibitors versus placebo, outcome: 1.3 Maximum walking distance.

Data on IMT and revascularisation were not reported in these studies. Comparison 2 - calcium antagonists versus placebo The third trial compared the calcium antagonist verapamil against placebo in 96 patients who had undergone peripheral arterial angioplasty (Schweizer 1998). SBP was measured in the arm and posterior tibial artery by means of continuous wave Doppler ultrasound in the PTCA-treated leg. The ankle brachial SBP ratio was then calculated. In terms of ABI there was no statistically sig-

nificant difference between the active drug and placebo immediately after angioplasty or at six weeks. However, six months after the angioplasty there was a marginal benefit on ABI in favour of the calcium antagonist, although the 95% CI fell exactly on zero (MD 0.04, 95% CI 0.00 to 0.08). The degree of diameter stenosis and arterial IMT six months after angioplasty showed a significant reduction with the use of verapamil (MD -21.6%, 95% CI -26.4 to -16.8; and MD -0.70 mm, 95% CI -0.86 to -0.54, respectively) (Figure 5; Figure 6, respectively) compared to placebo. Data on other outcomes were not reported in this study.

Figure 5. Forest plot of comparison: 2 Calcium antagonists versus placebo, outcome: 2.1 Degree of diameter stenosis.


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Figure 6. Forest plot of comparison: 2 Calcium antagonists versus placebo, outcome: 2.3 Arterial intimamedia thickness.

Comparison 3 - thiazide diuretics versus alphaadrenoceptor blocking drugs In the fourth study there was no significant difference in arterial IMT when the 27 men receiving the thiazide diuretic hydrochlorothiazide (HCTZ) were compared with the 29 men receiving the alpha-adrenoreceptor blocker doxazosin (MD -0.04 mm, 95% CI -0.11 to 0.03) (DAPHNE 2002). Data for other outcomes were not reported in this study. Comparison 4 - angiotensin-II receptor antagonist versus placebo The fifth study comparing the angiotensin-II receptor antagonist telmisartan against placebo in 36 patients (Zankl 2010) found a significant improvement in MWD after 12 months in the 18 patients treated with telmisartan compared to those receiving placebo (median 191 m, 95% CI 157 to 226 and 132 m, 95% CI 103 to 192, respectively; P < 0.001). There were no significant differences in ABI (median 0.60, 95% CI 0.60 to 0.77 and 0.60, 95% CI 0.56 to 0.77, respectively) or IMT (median 0.08 cm, 95% CI 0.07 to 0.09 and 0.09 cm, 95% CI 0.08 to 0.09, respectively) after 12 months between those receiving telmisartan or placebo. Data on other outcomes were not reported in this study. Comparison 5 - beta-adrenoreceptor blockers versus thiazide diuretics In the sixth study there were no significant differences between the 84 patients receiving the beta-adrenoreceptor blocker nebivolol and the 79 patients receiving the thiazide diuretic HCTZ after 24 weeks of treatment in change in IC distance (MD -1.3 m, 95% CI -19.04 to 16.44), change in absolute claudication distance (ACD) (MD -9.70 m, 95% CI -34.80 to 15.40), change in ABI (MD 0.02, 95% CI -0.06 to 0.03), all-cause mortality (OR 2.86, 95% CI 0.11 to 71.15) or non-fatal cardiovascular events (OR 0.94, 95% CI 0.06 to 15.28) (Diehm 2011). Data on other outcomes were not reported in this study. Comparison 6 - beta-adrenoreceptor blockers versus beta-adrenoreceptor blockers

In the NORMA study (NORMA 2011) comparing two betaadrenoreceptor blockers there were no significant differences after 36 weeks of treatment between the 52 patients receiving nebivolol and the 57 patients receiving metoprolol in IC distance (MD 5.50 m, 95% CI -23.30 to 34.30), ACD (MD -18.70 m, 95% CI 77.31 to 39.91), ABI (MD 0.01, 95% CI -0.07 to 0.09), all-cause mortality (OR 11.78, 95% CI 0.62 to 224.14) or revascularisation (OR 7.30, 95% CI 0.85 to 62.87). Data on other outcomes were not reported in this study.

Comparison 7 - calcium antagonist-based strategy versus beta-adrenoreceptor blocker-based strategy A subgroup analysis (INVEST 2003) among 2699 PAD patients in the INVEST study revealed no significant differences in the composite endpoints of death, non-fatal MI or non-fatal stroke (OR 0.90, 95% CI 0.76 to 1.07) or death, non-fatal MI or nonfatal stroke and revascularisation (OR 0.96, 95% CI 0.82 to 1.13) between the 1345 patients receiving a calcium antagonist-based strategy (verapamil SR ± trandolapril) compared to the 1354 patients receiving a beta-adrenoreceptor blocker strategy (atenolol ± HCTZ). Data on other outcomes were not reported in this study.

DISCUSSION Summary of main results This review found eight RCTs (Overlack 1994; Schweizer 1998; DAPHNE 2002; INVEST 2003; HOPE 2004; Zankl 2010; Diehm 2011; NORMA 2011) comparing at least one recognised class of anti-hypertensive treatment against placebo (Overlack 1994; Schweizer 1998; HOPE 2004; Zankl 2010) or two antihypertensive medications against each other (DAPHNE 2002; INVEST 2003; Diehm 2011; NORMA 2011) in patients with PAD as either the study population (Overlack 1994; Schweizer 1998; DAPHNE 2002; Zankl 2010; Diehm 2011; NORMA 2011) or a subgroup (INVEST 2003; HOPE 2004). Compared to placebo, ramipril significantly reduced the risk of cardiovascular events (combined endpoint of cardiovascular death, non-fatal


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MI or non-fatal stroke) (OR 0.72, 95% 0.58 to 0.91) (HOPE 2004) but there was no significant difference between anti-hypertensive treatment strategies on cardiovascular events (death, nonfatal MI or non-fatal stroke) in the subgroup analysis of PAD patients in the INVEST study (INVEST 2003). Verapamil significantly improved arterial IMT compared to placebo following arterial angioplasty (Schweizer 1998) but two other studies found no differences in arterial IMT with telmisartan compared to placebo (Zankl 2010) or HCTZ and doxazosin (DAPHNE 2002). Anti-hypertensives do not appear to improve pain-free walking distance (Overlack 1994; Diehm 2011; NORMA 2011) or ABI (Overlack 1994; Schweizer 1998; Zankl 2010; Diehm 2011; NORMA 2011).

Overall completeness and applicability of evidence Although there can be little question about the validity of outcome measures such as walking distance and cardiovascular events, some of the measures used in published studies (for example calf blood flow and ABI) might be regarded as surrogate endpoints. While both these measures are useful for measuring blood flow objectively in the affected limb, thus obtaining a diagnosis of the disease, subjective reporting of the progression of the disease by patients might well be the more important consideration in clinical practice. Two (INVEST 2003; HOPE 2004) of the eight included studies (Overlack 1994; Schweizer 1998; DAPHNE 2002; INVEST 2003; HOPE 2004; Zankl 2010; Diehm 2011; NORMA 2011) looked at hard clinical endpoints, such as cardiovascular events (INVEST 2003; HOPE 2004). Two other studies also reported data for all-cause mortality (Diehm 2011; NORMA 2011) or revascularisation (NORMA 2011), although these endpoints were not listed as outcomes in the study methods. In the HOPE study, ramipril significantly reduced the risk of cardiovascular events (combined endpoint of cardiovascular death, non-fatal MI and non-fatal stroke) by 28% when compared to placebo (OR 0.72, 95% CI 0.58 to 0.91) (Figure 3). In the PAD subgroup analysis of the INVEST study (INVEST 2003) there was no significant difference between a calcium antagonist-based strategy (verapamil ± trandolapril) and a beta-adrenoreceptor blocker-based strategy (atenolol ± HCTZ) in the composite endpoints of death, non-fatal MI or non-fatal stroke (OR 0.90, 95% CI 0.76 to 1.07) or death, non-fatal MI or non-fatal stroke plus revascularisation (OR 0.96, 95% CI 0.82 to 1.13). One study (Diehm 2011) also reported no significant differences in all-cause mortality or non-fatal cardiovascular events between nebivolol and HCTZ (OR 2.86, 95% CI 0.11 to 71.15 and OR 0.94, 95% CI 0.06 to 15.28, respectively). In the NORMA study (NORMA 2011) there were no significant differences between nebivolol and metoprolol in all-cause mortality (OR 10.67, 95% CI 0.56 to 203.18) and revascularisation (OR 7.30, 95% CI 0.85 to 62.87).

Three of the studies examining the effect of anti-hypertensives on arterial IMT reported conflicting results (Schweizer 1998; DAPHNE 2002; Zankl 2010). One (Schweizer 1998) demonstrated a significant improvement in arterial IMT with verapamil compared to placebo six weeks and six months following peripheral arterial angioplasty (Figure 6), while the other two (DAPHNE 2002; Zankl 2010) found no difference in arterial IMT between HCTZ and doxazosin (DAPHNE 2002) or telmisartan and placebo (Zankl 2010). Verapamil was also associated with a reduction in the degree of restenosis compared to placebo (Schweizer 1998) (Figure 5). Five studies (Overlack 1994; Schweizer 1998; Zankl 2010; Diehm 2011; NORMA 2011) examined the effects of the anti-hypertensives on ABI. Three (Overlack 1994; Schweizer 1998; Zankl 2010) compared the anti-hypertensives perindopril (Overlack 1994), verapamil (Schweizer 1998) and telmisartan (Zankl 2010) to placebo and all three found no significant difference in ABI between the active drug and placebo (Overlack 1994; Schweizer 1998; Zankl 2010) (Figure 4). Two studies (Diehm 2011; NORMA 2011) compared nebivolol to either HCTZ (Diehm 2011) or metoprolol (NORMA 2011) and both found no significant difference in ABI between the two antihypertensives. The reduction in the degree of narrowing within the affected artery that was seen with verapamil (Schweizer 1998) should be considered in the light of a very marginal improvement in ABI six months after angioplasty, and no data on symptoms. It is possible that although there was restenosis on placebo little deterioration in blood flow occurred due to other mechanisms such as the formation of new blood vessels, called collaterals, to take the blood to the feet. Three studies (Overlack 1994; Diehm 2011; NORMA 2011) investigating the effects of the anti-hypertensives ramipril (Overlack 1994) and nebivolol (Diehm 2011; NORMA 2011) compared to placebo (Overlack 1994), HCTZ (Diehm 2011) or metoprolol (NORMA 2011) reported no significant improvement in IC distance with treatment. These three studies (Overlack 1994; Diehm 2011; NORMA 2011) plus one other (Zankl 2010) also examined the effect of anti-hypertensives on MWD, IC distance plus metres walked in pain. Two studies (Diehm 2011; NORMA 2011) comparing two anti-hypertensives treatments reported no significant differences in MWD, while the other two studies (Overlack 1994; Zankl 2010) comparing active drug to placebo reported conflicting results. Overlack reported a significant improvement in MWD with placebo compared to ACE inhibitor (MD -46.00 m, 95% CI -69.74 to -22.26) (Overlack 1994) (Figure 4), while the other (Zankl 2010) found a significant improvement in the MWD with telmisartan compared to placebo (median 191 m, 95% CI 157 to 226 and 132 m, 95% CI 103 to 192, respectively; P < 0.001). Therefore, it appears that ACE inhibitors are effective in reducing the number of cardiovascular events (HOPE 2004), with no significant differences in cardiovascular events between anti-hypertensive regimens (INVEST 2003). In one study (Schweizer 1998) with blinded outcome assessment in hypertensive patients with


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PAD, verapamil appears to significantly improve arterial IMT and reduce the degree of restenosis six months after peripheral arterial angioplasty (Schweizer 1998). Anti-hypertensives do not appear to improve ABI or IC distance. There is conflicting evidence on the benefit of anti-hypertensives in improving MWD, with one study (Zankl 2010) reporting an improvement in MWD with telmisartan compared to placebo while another (Overlack 1994) demonstrated an improvement in MWD with placebo compared to ramipril. However, caution is warranted when interpreting the results given that four (Overlack 1994; Schweizer 1998; DAPHNE 2002; Zankl 2010) of the eight included studies had relatively small numbers of patients, ranging from 36 (Zankl 2010) to 98 (Schweizer 1998), and two (INVEST 2003; HOPE 2004) were subgroup analyses; many were underpowered for some or all of the outcomes assessed.

Potential biases in the review process Our search strategy included a comprehensive search of several electronic databases. In addition, we wrote to the authors of included and excluded studies requesting further data. Further, the titles and abstracts of all the studies identified by the search strategy were reviewed independently by two review authors and disagreements were resolved by consensus. Data extraction of the included studies was also undertaken independently by two review authors. Therefore, we believe that the potential for bias in the review process was minimal and that it is unlikely that we have missed important studies.

AUTHORS’ CONCLUSIONS Implications for practice

Quality of the evidence Overall the quality of the available evidence was unclear, primarily as a result of a lack of detail in the study reports on the randomisation and blinding procedures and incomplete outcome data (Figure 1; Figure 2). The one exception was the HOPE study (HOPE 2004), which demonstrated a low risk of bias except for a high attrition rate of 30%, although it used an ITT analysis. The DAPHNE study (DAPHNE 2002) also had a high risk of attrition bias with one quarter of all patients discontinuing study medication but a higher attrition rate with HCTZ than doxazosin. The PAD subgroup analysis of the INVEST study (INVEST 2003) was at high risk of performance and detection bias (Figure 2) as the trial was an open-label trial and medication could be uptitrated at the discretion of the physician, however the cardiovascular outcomes were independently adjudicated by a panel blinded to treatment allocation (INVEST 2003). In addition, the definition of PAD employed in INVEST was a documented history of PAD at baseline and no detailed information regarding the diagnosis of PAD was available (INVEST 2003). Further, there was a high risk of reporting bias in the subgroup analysis of INVEST (INVEST 2003) as only the two composite endpoints were reported and not the individual components of the composite endpoints which were also listed as outcomes. Three other studies (Overlack 1994; Schweizer 1998; NORMA 2011) also had a high risk of selective reporting (Figure 1; Figure 2). Overlack did not report the data collected for all the various subgroups, just the most disease-specific or relevant outcomes (Overlack 1994), and Schweizer did not report distance to claudication after treatment (Schweizer 1998). In the NORMA study (NORMA 2011) only the endpoint analyses were reported; the safety population data (those who received ≥ one dose of double-blind medication) described in the data analysis section was not included.

There has been much debate about the use of beta-adrenoreceptor blockers in intermittent claudication (IC), with early case reports suggesting that they should not be used at all. The limited data from the published trials suggest that there is very little evidence to support this practice. There is no evidence in this review to suggest that beta-adrenoreceptor blockers should not be used in the presence of peripheral arterial disease (PAD). However, this is due more to a lack of evidence from large studies rather than a definite lack of effect. The proven value of beta-adrenoreceptor blockade as a treatment for hypertension and following MI, combined with the lack of evidence for avoidance in PAD, suggests that the use of this class of drug in hypertensive patients with PAD may be warranted. If any doubt continues in the clinician’s mind, then a beta-adrenoreceptor blocker with intrinsic sympathomimetic activity (ISA) should probably be used. The positive effect of ACE inhibitors on cardiovascular events in patients at high cardiovascular risk cannot be ignored (HOPE 1996), although limited data are available in the hypertensive population per se. However, in a hypertensive patient with PAD some caution is needed where patients have associated renovascular disease. The evidence for benefit of other anti-hypertensive drug classes, specifically in patients with PAD and hypertension, is lacking. However, the current guidelines recommend lowering blood pressure in PAD patients to the same target blood pressure as for other high-risk groups in the absence of compelling data to the contrary. There is overwhelming evidence from clinical trials of the benefit of lowering systemic blood pressure to prevent cardiovascular events and mortality. The lack of data to date specifically examining outcomes in PAD patients should not detract from the overwhelming evidence of the benefit of treating hypertension and lowering blood pressure. The most recent European guidelines on the management of hypertension (ESH 2013) suggest that optimal


17

control of blood pressure in PAD patients is paramount and that the choice of anti-hypertensive is secondary to this. Expert consensus statements recommend total cardiovascular risk management in PAD patients employing anti-platelet agents and statins in addition to lifestyle modification and optimising blood pressure control.

Implications for research Clearly, as PAD and hypertension are significant problems in patients today and doubt exists about the treatment of one condition in the presence of the other, more research is indicated. Studies to date suggest that there are no differences in ABI between anti-hypertensive drugs (Diehm 2011; NORMA 2011) or compared to placebo (Overlack 1994; Schweizer 1998; Zankl 2010). Anti-hypertensives do not appear to worsen IC distance (Overlack 1994; Diehm 2011; NORMA 2011) but data on the effect of anti-hypertensives on maximum walking distance (MWD) is conflicting, although the sample sizes in these studies were small (ranging from 54 to 163 people). Since it would be unethical to withhold antihypertensive treatment from hypertensive patients with PAD, future large-scale studies in such patients are needed which specif-

ically measure walking distances and ankle brachial index (ABI) to examine whether the lowering of systemic blood pressure is associated with worsened limb perfusion leading to exacerbation of claudication symptoms and shorter walking distances, as well as examining the effects of such treatment on mortality and cardiovascular events. Such data could produce helpful recommendations regarding their future use. However, given that PAD patients are likely to be receiving polypharmacy, particularly statins and anti-platelet therapy, it may be difficult to disentangle the specific benefit of anti-hypertensive medication on cardiovascular events and mortality per se.

ACKNOWLEDGEMENTS The authors would like to thank the HOPE investigators for providing unpublished data relating to the number of PAD patients randomised to ramipril or placebo. In addition, the authors would like to thank Dr Cathryn Broderick of the Cochrane Peripheral Vascular Disease Group for her support and assistance with the update of this review.

REFERENCES

References to studies included in this review DAPHNE 2002 {published data only} Hoogerbrugge N, de Groot E, de Heide LH, de Ridder MA, Birkenhageri JC, Stijnen T, et al.Doxazosin and hydrochlorothiazide equally affect arterial wall thickness in hypertensive males with hypercholesterolaemia (the DAPHNE study). Doxazosin Atherosclerosis Progression Study in Hypertensives in the Netherlands. Netherlands Journal of Medicine 2002;60(9):354–61. Diehm 2011 {published data only} Diehm C, Pittrow D, Lawall H, for the study group. Effect of nebivolol vs. hydrochlorothiazide on the walking capacity in hypertensive patients with intermittent claudication. Journal of Hypertension 2011;29(7):1448–56. HOPE 2004 {published and unpublished data} ∗ Ostergren J, Sleight P, Dagenais G, Danisa K, Bosch J, Qilong Y, et al.for the HOPE study investigators. Impact of ramipril in patients with evidence of clinical or subclinical peripheral arterial disease. European Heart Journal 2004;25 (1):17–24. The HOPE Study Investigators. The HOPE (Heart Outcomes Prevention Evaluation) Study: the design of a large simple randomised trial of an angiotensin-converting enzyme inhibitor (ramipril) and vitamin E in patients at high risk of cardiovascular events. Canadian Journal of Cardiology 1996;12(2):127–37. Yusuf S, Dagenais G, Pogue J, Bosch J, Sleight P. Vitamin E supplementation and cardiovascular events in high-risk

patients. The Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. New England Journal of Medicine 2000;342(3):154–60. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. New England Journal of Medicine 2000;342 (3):145–53. INVEST 2003 {published data only} Bavry AA, Anderson D, Gong Y, Denardo SJ, CooperDeHoff RM, Handberg EM, et al.Outcomes among hypertensive patients with concomitant peripheral and coronary artery disease: Findings from the INternational VErapamil-SR/Trandolapril STudy. Hypertension 2010;55 (1):48–53. Pepine CJ, Handberg EM, Cooper-DeHoff RM, Marks RG, Kowey P, Messerli FH, et al.INVEST Investigators. A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil-Trandolspril Study (INVEST): A randomised controlled trial. JAMA 2003;290(21):2805–16. Pepine CJ, Handberg-Thurmond E, Marks RG, Conlon M, Cooper-DeHoof R, Volkers P, et al.Rationale and design of the International Verapamil SR/Trandolapril Study (INVEST): An internet-based randomised trial in coronary artery disease patients with hypertension. Journal of the American College of Cardiology 1998;32(5):1228–37.


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NORMA 2011 {published data only} Espinola-Klein C, Weisser G, Jagodzinski A, Savvidis S, Warnholtz A, Ostad MA, et al.β-blockers in patients with intermittent claudication and arterial hypertension: Results from the nebivolol or metoprolol in arterial occlusive disease trial. Hypertension 2011;58(2):148–54. Overlack 1994 {published data only} Overlack A, Adamczak M, Bachmann W, Bonner G, Bretzel RG, Derichs R, et al.ACE-inhibition with perindopril in essential hypertensive patients with concomitant diseases. The Perindopril Therapeutic Safety Collaborative Research Group. American Journal of Medicine 1994;97(2):126–34. Schweizer 1998 {published data only} Schweizer J, Kirch W, Koch R, Hellner G, Uhlmann K. Effect of high dose verapamil on restenosis after peripheral angioplasty. Journal of the American College of Cardiology 1998;31(6):1299–305. Zankl 2010 {published data only} Zankl AR, Ivandic B, Andrassy M, Volz HC, Krumsdorf U, Blessing E, et al.Telmisartan improves absolute walking distance and endothelial function in patients with peripheral artery disease. Clinical Research in Cardiology 2010;99(12): 787–94.

References to studies excluded from this review ABCD 2003 {published data only} Estacio RO, Jeffers BW, Hiatt WR, Biggerstaff SL, Gifford N, Schrier RW. The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with noninsulin-dependent diabetes and hypertension. New England Journal of Medicine 1998;338(10):645–52. Estacio RO, Savage S, Nagel NJ, Schrier RW. Baseline characteristics of participants in the Appropriate Blood Pressure Control in Diabetes trial. Controlled Clinical Trials 1996;17(3):242–57. Mehler PS, Coll JR, Estacio R, Esler A, Schrier RW, Hiatt WR. Intensive blood pressure control reduces the risk of cardiovascular events in patients with peripheral arterial disease and type 2 diabetes. Circulation 2003;107(5): 753–6. Ahimastos 2006 {published and unpublished data} Ahimastos AA, Dart AM, Lawler A, Blombery PA, Kingwell BA. Reduced arterial stiffness may contribute to angiotensin-converting enzyme inhibitor induced improvements in walking time in peripheral arterial disease patients. Journal of Hypertension 2008;26(5):1037–42. Ahimastos AA, Lawler A, Reid CM, Blombery PA, Kingwell BA. Brief communication: ramipril markedly improves walking ability in patients with peripheral arterial disease: a randomized trial. Annals of Internal Medicine 2006;144(9): 660–4. Ahimastos AA, Natoli AK, Lawler A, Blombery PA, Kingwell BA. Ramipril reduces large-artery stiffness in peripheral arterial disease and promotes elastogenic remodeling in cell culture. Hypertension 2005;45(6): 1194–9.

ASCOT 2005 {published and unpublished data} Dahlöf B, Sever PS, Poulter NR, Wedel H, Beevers DG, Caulfield M, et al.ASCOT Investigators. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the AngloScandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet 2005;366(9489):895–906. Sever PS, Dahlöf B, Poulter NR, Wedel H, Beevers G, Caulfield M, et al.Rationale, design, methods and baseline demography of participants of the Anglo-Scandinavian Cardiac Outcomes Trial. ASCOT investigators. Journal of Hypertension 2001;19(6):1139–47. Bernardi 1988 {published data only} Bernardi D, Bartoli P, Ferreri A, Geri AB, Ieri A. Assessment of captopril and nicardipine effects on chronic occlusive arterial disease of the lower extremity using Doppler ultrasound. Angiology 1988;39(11):942–52. Bogaert 1983 {published data only} Bogaert MG, Clement DL. Lack of influence of propranolol and metoprolol on walking distance in patients with chronic intermittent claudication. European Heart Journal 1983;4 (3):203–4. Bostrom 1986 {published data only} Bostrom PA, Janzon L, Ohlsson O, Westergren A. The effect of beta-blockade on leg blood flow in hypertensive patients with intermittent claudication. Angiology 1986;37 (3 Pt 1):149–53. Branchereau 1995 {published data only} Branchereau A, Rouffy J. Double-blind randomized controlled trial of ifenprodil tartrate versus placebo in chronic arterial occlusive disease of the legs at stage II of the Leriche and Fontaine classification. Journal des Maladies Vasculaires 1995;20(1):21–7. Brown 1998 {published data only} Brown MJ, Castaigne A, de Leeuw PW, Mancia G, Rosenthal T, Ruilope LM. Study population and treatment titration in the International Nifedipine GITS Study: Intervention as a Goal in Hypertension Treatment (INSIGHT). Journal of Hypertension 1998;16(12 Pt 2): 2113–6. Casiglia 1997 {published data only} Casiglia E, Petucco S, Pessina AC. Antihypertensive efficacy of amlodipine and enalapril and effects on peripheral blood flow in patients with essential hypertension and intermittent claudication. Clinical Drug Investigation 1997;13 Suppl 1: 97–101. Coto 1989 {published data only} Coto V, Cocozza M, Oliviero U, Lucariello A, Picano T, Coto F, et al.Clinical efficacy of picotamide in long-term treatment of intermittent claudication. Angiology 1989;40 (10):880–5. Coto 1991 {published data only} Coto V, Oliviero U, Cocozza M, Lucariello A, Picano T, Coto F. A comparative trial of ketanserin and nifedipine


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in hypertension and obstructive peripheral arteriopathy. Advances in Therapy 1991;8(3):133–40. Diehm 1993 {published data only} Diehm C, Jacobsen O, Amendt K. The effects of tertatolol on lipid profile. Cardiology 1993;83 Suppl 1:32–40. Domschky 1977 {published data only} Domschky K, Nelson M, Dammhayn B, Terjung E. Multicentre double blind study concerning flunarizine versus placebo in patients with cerebral and peripheral circulatory disorders. Medizinische Welt 1977;28(23): 1062–4. Gastmann 1987 {published data only} Gastmann U, Lehmann M, Staiger J, Keul J. Influence of the calcium antagonist nisoldipin on the sympathetic activity and the energy metabolism at rest and during walking stress in patients with peripheral arterial of the legs and healthy control subjects [Abstract only]. Zeitschrift fur Kardiologie 1987;76 Suppl 2:13. Hiatt 1985 {published data only} Hiatt WR, Stoll S, Nies AS. Effect of beta-adrenergic blockers on the peripheral circulation in patients with peripheral vascular disease. Circulation 1985;72(6): 1226–31. Ingram 1982 {published data only} Ingram DM, House AK, Thompson GH, Stacey MC, Castleden WM, Lovegrove FT. Beta-adrenergic blockade and peripheral vascular disease. Medical Journal of Australia 1982;1(12):509–11. Jageneau 1977 {published data only} Jageneau A, Haag F. Flunarizine versus placebo in patients with circulatory disorders of the lower extremities: double blind study. Medizinische Welt 1977;28(23):1050–5. Kalus 1995 {published data only} Kalus U, Jung F, Scheurer K, Koscielny J, Radtke H, Kiesewetter H, et al.The alpha and beta blocker carvediol in the treatment of hypertensive patients with POAD. Clinical Hemorheology 1995;15(5):570. Klieber 1986 {published data only} Klieber M, Resch F. Comparative studies of the effect of a cardioselective and a noncardioselective beta-blocker on peripheral circulation in patients with arterial occlusive disease [Vergleichende Untersuchengen uber die Werkung eines Kardioselektiven und eines Nichtkardioselektiven Betablockers auf die Periphere Durchblutung von Patienten mit Arterieller Verschlusskrankheit]. Weiner Klinische Wochenschrift 1986;98(3):70–3. Larsen 1969 {published data only} Larsen OA, Lassen NA. Medical treatment of occlusive arterial disease of the legs. Walking exercise and medically induced hypertension. Angiologica 1969;6(5):288–301. Laurent 1994 {published data only} Laurent S, Becquemont L, Laloux B, Asmar R, Hugue C, Vayssairat M, et al.Haemodynamic effects of chronic treatment by cilazapril in normotensive patients with obliterative arterial disease of the lower limbs [Effets

hemodynamiques d’un traitement chronique par le cilazapril chez les malades normotendus atteints d’arteriopathie obliiterante des membres inferieurs]. Archives des Maladies du Coeur et des Vaisseaux 1994;87(8):987–90. Leeman 1995 {published data only} Leeman M, Degaute JP. Invasive haemodynamic evaluation of sublingual captopril and nifedipine in patients with arterial hypertension after abdominal aortic surgery. Critical Care Medicine 1995;23(5):843–7. Lepantalo 1983 {published data only} Lepantalo M, Totterman KJ. Effect of long term betaadrenergic-blockade on calf blood flow in hypertensive patients. Clinical Physiology 1983;3(1):35–42. Lepantalo 1984 {published data only} Lepantalo M, von Knorring J. Walking capacity of patients with intermittent claudication during chronic antihypertensive treatment with metoprolol and methyldopa. Clinical Physiology 1984;4(4):275–82. Lepantalo 1985a {published data only} Lepantalo M. Beta blockade and intermittent claudication. Acta Medica Scandinavica. Supplementum 1985;700:1–48. ∗ Lepantalo M. Chronic effects of labetolol, pindolol and propranolol on calf blood flow in intermittent claudication. Clinical Pharmacology and Therapeutics 1985;37(1):7–12. Lepantalo M, Lindstrom BL, Totterman KJ. Adrenoreceptor blocking drugs and cold feet in intermittent claudication. Vasa 1986;15(2):135–7. Lepantalo 1985b {published data only} Lepantalo M, Aromaa A, Klaukka T, Lukkari E. Does betablockade provoke intermittent claudication?. Acta Medica Scandinavica 1985;218(1):35–9. Liakishev 2008 {published data only} Liakishev AA. Telmisartan, ramipril, or both in patients at high risk for vascular events. Results of the ONTARGET trial [Russian]. Kardiologiia 2008;48(5):72. Lievre 1996 {published data only} Lievre M, Azoulay S, Lion L, Morand S, Girre JP, Boissel JP. A dose-effect study of beraprost sodium in intermittent claudication. Journal of Cardiovascular Pharmacology 1996; 27(6):788–93. LIFE 2002 {published and unpublished data} Dahlöf B, Devereux R, de Faire U, Fyhrquist F, Hedner T, Ibsen H, et al.The Losartan Intervention For Endpoint reduction (LIFE) in Hypertension study: rationale, design, and methods. The LIFE Study Group. American Journal of Hypertension 1997;10(7 Part 1):705–13. Dahlöf B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U, et al.LIFE Study Group. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002;359(9311):995–1003. Liu 1997 {published data only} Liu Y, Opitz-Gress A, Rott A, Liewald F, Sunder-Plassmann L, Lehmann M, et al.Effect of felodipine on regional blood supply and collateral vascular resistance in patients with


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peripheral arterial occlusive disease. Vascular Medicine 1997;2(1):13–8. Mann 1998 {published data only} Mann J, Julius S. The Valsartan Antihypertensive Longterm Use Evaluation (VALUE) trial of cardiovascular events in hypertension. Rationale and design. Blood Pressure 1998; 7(3):176–83. Natali 1989 {published data only} Natali J, Kieny R, Le Bas P, Benhamou M, Molkhou JM. Ifenprodil tartrate in the treatment of occlusive arteriopathies of the lower limbs. Results of a prospective double-blind controlled multi-centre trial [Le tartrate d’ifenprodil dans le traitement des arteriopathies obliterantes des membres inferieures]. Annales de Cardiologie et d’Angeiologie 1989;38(6):339–42. Nelson 1978 {published data only} Nelson M, DeWitz G, Dom J, Hoerig CH. Trial of the activity of Sibelium (flunarizine) in circulatory disorders. Medizinische Welt 1978;29(29-30):1175–81. Novo 1985 {published data only} Novo S, Pinto A, Galati D, Giannola A, Forte G, Strano A. Effects of chronic administration of selective betablockers on peripheral circulation of the lower limbs in patients with essential hypertension. International Angiology 1985;4(2): 229–34. Novo 1986 {published data only} Novo S, Alaimo G, Abrignani MG, Giordano U, Avellone G, Pinto A, et al.Effects of ketanserin on blood pressure, peripheral circulation and haemocoagulative parameters in essential hypertensives with or without arteriosclerosis obliterans of the lower limbs. International Journal of Clinical Pharmacology Research 1986;6(3):199–211. Novo 1996 {published data only} Novo S, Abrignani MG, Pavone G, Zamueli M, Pernice C, Geraci AM, et al.Effects of captopril and ticlopidine, alone or in combination, in hypertensive patients with intermittent claudication. International Angiology 1996;15 (2):169–74. ONTARGET 2008 {published and unpublished data} Bohm M, Baumhakel M, Teo K, Sleight P, Probstfield J, Gao P, et al.ONTARGET/TRANSCEND Erectile Dysfunction Substudy Investigators. Erectile dysfunction predicts cardiovascular events in high-risk patients receiving telmisartan, ramipril, or both: The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial/Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (ONTARGET/TRANSCEND) Trials. Circulation 2010; 121(12):1439–46. Cowan BR, Young AA, Anderson C, Doughty RN, Krittayaphong R, Lonn E, et al.ONTARGET Investigators. Left ventricular mass and volume with telmisartan, ramipril, or combination in patients with previous atherosclerotic events or with diabetes mellitus (from the ONgoing Telmisartan Alone and in combination with Ramipril

Global Endpoint Trial (ONTARGET). American Journal of Cardiology 2009;104(11):1484–9. Teo K, Yusuf S, Sleight P, Anderson C, Mookadam F, Ramos B, et al.ONTARGET/TRANSCEND Investigators. Rationale, design, and baseline characteristics of 2 large, simple, randomized trials evaluating telmisartan, ramipril, and their combination in high-risk patients: the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial/Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (ONTARGET/TRANSCEND) trials. American Heart Journal 2004;148(1):52–61. ∗ The ONTARGET Investigators, Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, Schumacher H, et al.Telmisartan, ramipril, or both in patients at high risk for vascular events. New England Journal of Medicine 2008;358(15):1547–59. Yu LT, Zhu J, Tan HQ, Wang GG, Teo KK, Liu S, et al.Telmisartan, ramipril, or both in high-risk Chinese patients: analysis of ONTARGET China data. Chinese Medical Journal 2011;124(12):1763–8. OPERA 2002 {published data only} Kostis JB, Cobbe S, Johnston C, Ford I, Murphy M, Weber M, et al.OPERA Study Group. Omapatrilat in Persons with Enhanced Risk of Atherosclerotic events. Design of the Omapatrilat in Persons with Enhanced Risk of Atherosclerotic events (OPERA) trial. American Journal of Hypertension 2002;15(2 Pt 1):193–8. Panzner 1992 {published data only} Panzner B, Haringer E. Efficacy and tolerability of celiprolol and enalapril in patients with essential hypertension. Journal of Drug Development 1992;5(2):83–7. POISE 2008 {published data only} POISE study group. Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery (POISE trial): a randomised controlled trial. Lancet 2008; 371(9627):1839–47. Reichert 1975 {published data only} Reichert N, Shibolet S, Adar R, Gafni J. Controlled trial of propranolol in intermittent claudication. Clinical Pharmacology and Therapeutics 1975;17(5):612–5. Roberts 1987 {published data only} Roberts DH, Tsao Y, McLoughlin GA, Breckenridge A. Placebo-controlled comparison of captopril, atenolol, labetalol and pindolol in hypertension complicated by intermittent claudication. Lancet 1987;2(8560):650–3. Roberts 1992 {published data only} Roberts DH, Tsao Y, Linge K, Chatlani PT, McLoughlin GA, Breckenridge AM. Double-blind comparison of captopril or nifedipine in hypertension complicated by intermittent claudication. British Journal of Clinical Pharmacology 1988;25(5):631P–2P. ∗ Roberts DH, Tsao Y, Linge K, McLoughlin GA, Breckenridge A. Double-blind comparison of captopril with nifedipine in hypertension complicated by intermittent claudication. Angiology 1992;43(9):748–56.


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Rouffy 1989 {published data only} Rouffy J, Djian F, Barret A, Branchereau A, Chevalier JM, Cristol R, et al.Ifenprodil tartrate for the treatment of chronic obliterating arteriosclerosis of the lower limbs with intermittent claudication. A multicentre, prospective, randomised, double-blind trial versus placebo [Le tartrate d’ifenprodil dans le traitement de l’arteriopathie chronique obliterante des membres inferieurs. Au stade de la claudication intermittente]. Semaines des Hopitaux 1989;65 (33):2071–6. Schweizer 1996 {published data only} Schweizer J, Kaulen R, Altman E, Nierade A, Nanning T. Are beta-blockers generally contraindicated in patients with peripheral arterial occlusive disease? [Sind Betablocker bei Patienten mit Peripherer Arterieller Verschlusskrankheit Generell Kontraindiziert?]. Zeitschrift fur Kardiologie 1996; 85(3):193–7. ∗ Schweizer J, Kaulen R, Nierade A, Altman E. Beta blockers and nitrates in patients with peripheral arterial occlusive disease: long term findings. Vasa 1997;26(1):43–6. Siniscalchi 1993 {published data only} Siniscalchi N, De Nicola A, Misso L, Cerciello T, Carbone L, Molisso A. Treatment and monitoring of obstructive peripheral arterial disease in elderly with systolic hypertension. International Angiology 1993;12:76. Smith 1982 {published data only} Smith RS, Warren DJ. Effect of beta-blocking drugs on peripheral blood flow in intermittent claudication. Journal of Cardiovascular Pharmacology 1982;4(1):2–4. Solomon 1991 {published data only} Solomon SA, Ramsay LE, Yeo WW, Parnell L, MorrisJones W. Beta blockade and intermittent claudication: placebo controlled trial of atenolol and nifedipine and their combination. BMJ 1991;303(6810):1100–4. Spence 1993 {published data only} Spence JD, Arnold MO, Munoz CE, Vishwanatha A, Huff M, Derose G, et al.Angiotensin-converting enzyme inhibition with cilazapril does not improve blood flow, walking time, or plasma lipids in patients with intermittent claudication. Journal of Vascular Medicine and Biology 1993; 4(1):23–8. Staessen 1978 {published data only} Staessen AJ. Flunarizine and cinnarizine in pharmacotherapy of circulatory disturbances. Ars Medici Internationaal Tijdschrift voor Praktische Therapie 1978;7(5):433–45. Stumpe 1993 {published data only} Stumpe KO, Overlack A. A new trial of the efficacy, tolerability and safety of angiotensin-converting enzyme inhibition in mild systemic hypertension with concomitant diseases and therapies. Perindopril Therapeutic Safety Study Group (PUTS). American Journal of Cardiology 1993; 71(17):32E–7E. Stumpe 1995 {published data only} Stumpe KO, Ludwig M, Heagerty AM, Kolloch RE, Mancia G, Safar M, et al.Vascular wall thickness in hypertension: the Perindopril Regression of Vascular

Thickening European Community Trial: PROTECT. American Journal of Cardiology 1995;76(15):50E–4E. Sutton-Tyrell 1995 {published data only} Sutton-Tyrell K, Alcorn HG, Herzog H, Kelsey SF, Kuller LH. Morbidity, mortality, and antihypertensive treatment effects by extent of atherosclerosis in older adults with isolated systolic hypertension. Stroke 1995;26(8):1319–24. Svendsen 1986 {published data only} Svendsen TL, Jelnes R, Tonnesen KH. Is adrenergic betareceptor blockade contraindicated in patients with intermittent claudication?. Acta Medica Scandinavica. Supplementum 1985;217(s693):129–32. ∗ Svendsen TL, Jelnes R, Tonnesen KH. The effects of acebutolol and metoprolol on walking distances and distal blood pressure in hypertensive patients with intermittent claudication. Acta Medica Scandinavica 1986;219(2): 161–5. Takeda 2010 {published data only} Takeda K, Ohshima M, Matsumoto S, Yagi T, Morigchi J, Takanashi Y. Effects of one-year treatment with calcium channel blocker or angiotensin II receptor blocker on function and stiffness of left ventricle, central and peripheral arteries in patients with essential hypertension. Therapeutic Research 2010;31(3):351–62. VALUE 2006 {published data only} Julius S, Kjeldsen SE, Weber M, Brunner HR, Ekman S, Hansson L, et al.VALUE trial group. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet 2004;363(9426):2022–31. Mann J, Julius S. The Valsartan Antihypertensive Longterm Use Evaluation (VALUE) trial of cardiovascular events in hypertension. Rationale and design. Blood Pressure 1998; 7(3):176–83. Zanchetti A, Julius S, Kjeldsen S, McInnes GT, Hua T, Weber M, et al.Outcomes in subgroups of hypertensive patients treated with regimens based on valsartan and amlodipine: An analysis of findings from the VALUE trial. Journal of Hypertension 2006;24(11):2163–8. Van de Ven 1994 {published data only} Van de Ven LL, Van Leeuwen JT, Smit AJ. The influence of chronic treatment with beta-blockade and angiotensin converting enzyme inhibition on the peripheral blood flow in hypertensive patients with and without concomitant intermittent claudication. A comparative cross-over trial. Vasa 1994;23(4):357–62. Weibull 1992 {published data only} Weibull H, Bergentz S, Bergqvist D, Hulthen L, Manhem P, Jonsson K, et al.Percutaneous transluminal angioplasty vs reconstructive renovascular surgery in atherosclerotic unilateral renal artery stenosis - a prospective randomised study. Journal of Vascular Surgery 1992;15(6):1058. Winterfeld 1984 {published data only} Winterfeld HJ, Strangfeld D, Siewert H, Schmidt HH, Mederacke W. Behavior of blood pressure and peripheral hemodynamics in interval therapy in untreated and


22

propranolol-treated patients with arterial circulatory disorders of the lower extremities]. [German]. Zeitschrift fur die Gesamte Innere Medizin und Ihre Grenzgebiete 1984; 39(18):447–50.

References to studies awaiting assessment Ahimastos 2013 {published data only} Ahimastos AA, Walker PJ, Askew C, Leicht A, Pappas E, Blombery P, et al.Effect of ramipril on walking times and quality of life among patients with peripheral artery disease and intermittent claudication: a randomized controlled trial. JAMA 2013;309(5):453–60.

Additional references Bauwens 1989 Bauwens F, Duprez D, Van Wassenhove A, Brusselmans F, Clement DL. Localisation and risk factors of peripheral arterial occlusive disease in the female. International Angiology 1989;8(1):32–5. Bavry 2010a Bavry AA, Anderson RD, Gong Y, Denardo SJ, CooperDeHoff RM, Handberg EM, et al.Outcomes among hypertensive patients with concomitant peripheral and coronary artery disease: Findings from the INternational VErapamil-SR/Trandolapril STudy. Hypertension 2010;55 (1):48–53. Binaghi 1994 Binaghi F, Fronteddu PF, Cannas F, Caredda E, Uras A, Garau P, et al.Prevalence of peripheral arterial occlusive disease and associated risk factors in a sample of southern Sardinian population. International Angiology 1994;13(3): 233–45. Bowlin 1997 Bowlin SJ, Medalie JH, Flocke SA, Zyzanski SJ, Yaari S, Goldbourt U. Intermittent claudication in 8343 men and 21-year specific mortality follow-up. Annals of Epidemiology 1997;7(3):180–7. Breckenridge 1992 Breckenridge A, Roberts D, Walley T. Different vasodilating mechanisms - different peripheral effects?. Journal of Cardiovascular Pharmacology 1992;19 Suppl 1:S23–6. Cheng 1999 Cheng SW, Ting AC, Lau H, Wong J. Epidemiology of atherosclerotic peripheral arterial occlusive disease in Hong Kong. World Journal of Surgery 1999;23(2):202–6. Clement 2007 Clement DL, Debuyzere ML. How to treat hypertension in patients with peripheral artery disease. Current Hypertenssion Reports 2007;9:190–5. Criqui 1992 Criqui MH, Langer RD, Fronek A, Feigelson HS, Klauber MR, McCann TJ, et al.Mortality over a period of 10 years in patients with peripheral arterial disease. New England Journal of Medicine 1992;326:381–6.

Dormandy 2000 Dormandy JA, Rutherford RB. Management of peripheral arterial disease (PAD). TASC Working Group. TransAtlantic Inter-Society Consensus (TASC). Journal of Vascular Surgery 2000;31:S1–S296. ESH 2013 Mancia G, Fagard R, Narkiewicz K, Redón J, Zanchetti A, Böhm M, et al.2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Journal of Hypertension 2013;31: 1281–357. Feringa 2006 Feringa HH, van Waning VH, Bax JJ, Elhendy A, Boersma E, Schouten O, et al.Cardioprotective medication is associated with improved survival in patients with peripheral arterial disease. Journal of the American College of Cardiology 2006;47:1182–7. Fontaine 1954 Fontaine R, Kim M, Kieny R. Surgical treatment for peripheral vascular disease [Die chirurgische Behandlung der peripheren Durchblutungsstörungen]. Helvetica Chirurgica Acta 1954;5/6:499–533. Fowkes 1992 Fowkes FG, Housley E, Riemersma RA, Macintyre CC, Cawood EH, Prescott RJ, et al.Smoking, lipids, glucose intolerance, and blood pressure as risk factors for peripheral atherosclerosis compared with ischemic heart disease in the Edinburgh Artery Study. American Journal of Epidemiology 1992;135(4):331–40. Fowkes 2013 Fowkes FG, Rudan D, Rudan I, Aboyans V, Denenberg JO, McDermott MM, et al.Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis. Lancet 2013;382(9901):1329–40. [DOI: 10.1016/S0140-6736 (13)61249-0] Higgins 2011 Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org. Hirsch 2001 Hirsch AT, Criqui MH, Treat-Jacobson D, Regensteiner JG, Creager MA, Olin JW, et al.Peripheral arterial disease detection, awareness, and treatment in primary care. JAMA 2001;286:1317–24. Hjalmarson 1997 Hjalmarson A. Effects of beta blockade on sudden cardiac death during acute myocardial infarction and the postinfarction period. American Journal of Cardiology 1997; 80(9B):35J–9J. HOPE 1996 The HOPE Study Investigators. The HOPE (Heart Outcomes Prevention Evaluation) Study: the design of a


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large, simple randomised trial of an angiotensin-converting enzyme inhibitor (ramipril) and vitamin E in patients at high risk of cardiovascular events. Canadian Journal of Cardiology 1996;12(2):127–37. INVEST 2006 Pepine CJ, Kowey PR, Kupfer S, Kolloch RE, Benetos A, Mancia G, et al.Predictors of adverse outcome among patients with hypertension and coronary artery disease. Journal of the American College of Cardiology 2006;47: 547–51. Johnston 1988 Johnston KW, Rae M, Steiner G, Kalman PG, Schwartz L, Hill ME, et al.An atherosclerosis risk factor assessment program for patients with peripheral arterial occlusive disease. Annals of Vascular Surgery 1988;2(2):101–7. Kannel 1974 Kannel WB. Role of blood pressure in cardiovascular morbidity and mortality. Progress in Cardiovascular Diseases 1974;17(1):5–24. Kannel 1996 Kannel WB. The demographics of claudication and the aging of the American population. Vascular Medicine 1996; 1(1):60–4. Makin 2001 Makin A, Lip GY, Silverman S, Beevers DG. Peripheral vascular disease and hypertension: a forgotten association?. Journal of Human Hypertension 2001;15(7):447–54. Makin 2002 Makin A, Silverman SH, Lip GYH. Peripheral vascular disease and Virchow’s triad for thrombogenesis. QJM 2002; 95(4):199–210. McGill 1998 McGill HC Jr, McMahan CA, Tracy RE, Oalmann MC, Cornhill JF, Herderick EE, et al.Relation of a postmortem renal index of hypertension to atherosclerosis and coronary artery size in young men and women. Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group. Arteriosclerosis Thrombosis and Vascular Biology 1998;18(7):1108–18. Murabito 2005 Murabito JM, Evans JC, D’Agostino RB Sr, Wilson PW, Kannel WB. Temporal trends in the incidence of intermittent claudication from 1950 to 1999. American Journal of Epidemiology 2005;162:430–7. Novo 1992 Novo S, Avellone G, Di Garbo V, Abrignani MG, Liquori M, Panno AV, et al.Prevalence of risk factors in patients with peripheral arterial disease. A clinical and epidemiological evaluation. International Angiology 1992;11(3):218–29.

Pande 2011 Pande RL, Perlstein TS, Beckman JA, Creager MA. Secondary prevention and mortality in peripheral artery disease: National Health and Nutrition Examination Study, 1999 to 2004. Circulation 2011;124:17–23. Radack 1991 Radack K, Deck C. Beta-adrenergic blocker therapy does not worsen intermittent claudication in subjects with peripheral arterial disease. A meta-analysis of randomized controlled trials. Archives of Internal Medicine 1991;151: 1769–76. Reunanen 1982 Reunanen A, Takkunen H, Aromaa A. Prevalence of intermittent claudication and its effect on mortality. Acta Medica Scandinavica 1982;211(4):249–56. Simon 1986 Simon AC, Levenson J, Maarek B, Bouthier J, Safar ME. Evidence of early changes of the brachial artery circulation in borderline hypertension. Journal of Cardiovascular Pharmacology 1986;8 Suppl 5:S36–8. Singer 2008 Singer DR, Kite A. Management of hypertension in peripheral arterial disease: does the choice of drugs matter?. European Journal of Vascular and Endovascular Surgery 2008; 35:701–8. TASC-II 2007 Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG, TASC II Working Group. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). Journal of Vascular Surgery 2007;45 Suppl S:S5–67. Violi 1996 Violi F, Criqui M, Longoni A, Castiglioni C. Relation between risk factors and cardiovascular complications in patients with peripheral vascular disease. Results from the A.D.E.P. study. Atherosclerosis 1996;120(1-2):25–35.

References to other published versions of this review Lane 2009 Lane DA, Lip GY. Treatment of hypertension in peripheral arterial disease. Cochrane Database of Systematic Reviews 2009, Issue 4. [DOI: 10.1002/ 14651858.CD003075.pub2] Lip 2003 Lip GYH, Makin AJ. Treatment of hypertension in peripheral arterial disease. Cochrane Database of Systematic Reviews 2003, Issue 2. [DOI: 10.1002/ 14651858.CD003075] ∗ Indicates the major publication for the study


24

CHARACTERISTICS OF STUDIES

Characteristics of included studies [ordered by study ID] DAPHNE 2002 Methods

DAPHNE study: single-blind placebo medication for first six weeks, followed by doubleblind randomisation Method of randomisation not mentioned Dropouts: 12 (29.3%) from the doxazosin group; 12 (30.8%) from the hydrochlorothiazide (HCTZ) group Both drugs could be doubled in dose at two-weekly intervals until the goal diastolic blood pressure of 90 mmHg was achieved

Participants

Location: outpatient clinics at two hospitals in the Netherlands Inclusion criteria: peripheral arterial disease (PAD) patients, 80 men aged 45-70 years Doxazosin group: 41 (8 dropouts, n = 29) HCTZ group: 39 (12 dropouts, n = 27)

Interventions

Doxazosin 1 mg, 2 mg, 4 mg, 8 mg, 16 mg once daily (od) or HCTZ 12.5 mg, 25 mg, 50 mg, 100 mg. The dose of either doxazosin or HCTZ was increased at two-weekly intervals until the target blood pressure was achieved Duration: three years

Outcomes

Arterial intima-media thickness (IMT) of 20 longitudinal arterial wall segments of the carotid and femoral arteries

Notes

For the outcome arterial (IMT) the data presented are the change from baseline to threeyears follow-up, for the average of 20 mean far and near walls of carotid and femoral arteries combined for the two treatment groups. However, data are also presented for carotid and femoral arteries separately, and combined arteries for each of the following: average of maximum far and near walls, average of far walls, and average of near walls. There was a significant change in IMT for each of the groups of arteries examined, for both the HCTZ and doxazosin groups. Data for the change in arterial IMT from baseline to three-years follow-up are only available for 27 patients receiving HCTZ and 29 patients receiving doxazosin For the outcome peripheral vascular surgery, the type of surgery was not specified. Five patients in each treatment group (HCTZ n = 31; doxazosin n = 33) received peripheral vascular surgery for progressive PAD

Risk of bias Bias

Authors’ judgement

Support for judgement

Random sequence generation (selection Unclear risk bias)

No description given, only that patients were randomised

Allocation concealment (selection bias)


Unclear risk


25

DAPHNE 2002

(Continued)

Blinding (performance bias and detection Unclear risk bias) Participant

Trial described as double-blind but no description given

Blinding (performance bias and detection Unclear risk bias) Physician


Blinding (performance bias and detection Unclear risk bias) Outcome assessor

No information given regarding the blinding of the outcome assessor

Incomplete outcome data (attrition bias) All outcomes

High risk

Similar number of dropouts in both groups but follow-up data only available for 69.2% and 70.7% in the HCTZ and doxazosin groups, respectively

Selective reporting (reporting bias)

Unclear risk

The authors reported all the data for the measures they stated in the methods section of the paper

Other bias

Unclear risk

Measurement bias: measurements of the IMT from the carotid and femoral arteries were “quality controlled by repeated measurement procedure”, but intra- and interobserver variability was not reported in this paper

Diehm 2011 Methods

Multi-centre, prospective, randomised, double-blind, active-controlled trial

Participants

Location: multi-centre, all sites in Germany, participants recruited April 2006 to December 2008 Inclusion criteria: patients aged ≥ 40 years with essential hypertension and confirmed PAD patients at Fontaine Stage II. Hypertension criteria checked twice. First at screening (visit 1), hypertension was defined as systolic blood pressure (SBP) 140 - 179 mmHg and diastolic blood pressure (DBP) 90 -109 mmHg with or without treatment with anti-hypertensive drugs. Second check was at baseline (visit 3), SBP > 130 mmHg and DBP > 85 mmHg. Other inclusion criteria: aspirin 100 mg and/or clopidogrel 75 mg or phenprocoumon (stable for ≥ 3 months) stable background cardiovascular medication; treadmill variability in absolute claudication distance (ACD) ≤ 25% between screening and baseline (week 4); ACD between 100 m and 300 m at baseline Although 177 participants were randomised only results report intention-to-treat (ITT) analysis on n = 163. 163 participants, mean (SD) age 66.3 (9.2), all Caucasian and 125 (76.7%) men Nebivolol group: 84 (19 dropouts, n = 65 in per protocol analyses). Mean (SD) age 66. 9 (9.8) years; 68 (81.0%) men


26

Diehm 2011

(Continued)

HCTZ group: 79 (17 dropouts, n = 62 in per protocol analyses). Mean (SD) age 65.5 (8.5) years; 57 (72.1%) men Interventions

Nebivolol 5 mg od or HCTZ 25 mg od Duration: 6 months

Outcomes

Primary outcome: % change in IC distance (distance walked in metres until onset of pain) between baseline and week 28 Secondary outcomes: ACD (pain-free metres plus distance walked with pain) between baseline and week 28; quality of life; adverse events and serious adverse events (which included cardiovascular outcomes). Although not listed as secondary endpoints the paper also reports on ABI and all-cause mortality which are of interest to this Cochrane review

Notes

Although 177 participants were randomised, results only report ITT analysis on n = 163. No detail given on the 14 patients randomised who are not included in the ITT analyses. Both treatment groups were well-balanced in terms of baseline differences. The only significant baseline difference was in concomitant use of amlodipine (25.3% versus 10.3% in the nebivolol vs HCTZ group, respectively). PAD defined as history of typical IC for ≥ 6 months; actual proven PAD by objective means such as haemodynamics and non-invasive imaging or angiography; history of previous lower extremity vascular intervention; ABI of the worse leg < 0.90 All data reported in this Cochrane review are for ITT analyses (as is the convention for RCTs)

Risk of bias Bias



Random sequence generation (selection Low risk bias)

Randomised 1:1 using a computer-generated randomisation list


Low risk

Randomised 1:1 using a computer-generated randomisation list

Blinding (performance bias and detection Low risk bias) Participant

Trial described as double-blind and the nebivolol and HCTZ tablets were manufactured to be identical in size and appearance

Blinding (performance bias and detection Low risk bias) Physician

Double-blind trial, tablets identical in appearance and allocation done by computergenerated randomisation list


No detail given on the blinding of the outcome assessors


177 participants were randomised yet ITT analyses were only conducted on n = 163.

Unclear risk


27

Diehm 2011

(Continued)

Per protocol analyses were conducted on n = 127 (n = 65 on nebivolol and n = 62 on HCTZ); therefore 36 participants discontinued study medication (n = 19 on nebivolol and n = 17 on HCTZ) Selective reporting (reporting bias)

Unclear risk

Data were reported on all the outcomes mentioned in the Methods of the study. Additional outcomes are reported in the results section. Data were not available for 14 randomised participants with no explanation given for this missing data

Other bias

Unclear risk

Of the 266 participants screened only 177 (66.5%) were randomised

HOPE 2004 Methods

Mutli-centre, randomised, double-blind, placebo-controlled, two-by-two factorial trial

Participants

Location: 267 centres in 19 countries in North and South America and Europe HOPE participants were aged ≥ 55 years with existing cardiovascular disease or diabetes mellitus and an additional coronary risk factor (smoking, hypertension, hypercholesterolaemia/low HDL/microalbuminuria) but no heart failure or left ventricular dysfunction Number of patients: 1725 PAD patients Mean (SD) age: 66.7 (6.8) years; 1247 (72.3%) male PAD was defined as either IC with ABI < 0.9, or previous vascular intervention or limb amputation for PAD Number of PAD patients randomised to ramipril or placebo not stated in HOPE 2004 paper. Unpublished data provided by the authors Ramipril: 836 (48.5%) Placebo: 889 (51.5%)

Interventions

Single-blind run-in period for 7-10 days with ramipril 2.5 mg daily. If tolerated, randomised to ramipril 10 mg od (starting dose of 2.5 mg for 7 days, 5 mg for three weeks, then 10 mg) or matching placebo Duration: 4.5 years

Outcomes

Primary outcomes: cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke Secondary endpoints: all primary endpoints individually or all-cause mortality, heart failure hospitalisations, or diabetic complications

Notes

Heart Outcomes Prevention Evaluation (HOPE) We wish to thank Professor Östergren and colleagues for providing additional data on the PAD patients included in the HOPE trial

Risk of bias Treatment of hypertension in peripheral arterial disease (Review) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

28

HOPE 2004

(Continued)

Bias




Randomised using a central telephone service


Low risk

Randomised using a central telephone service

Blinding (performance bias and detection Low risk bias) Participant

Double-blind trial. ’Randomised using a central telephone service and patients given either ramipril or matching placebo’

Blinding (performance bias and detection Low risk bias) Physician

Double-blind trial. ’Randomised using a central telephone service and patients given either ramipril or matching placebo’

Blinding (performance bias and detection Low risk bias) Outcome assessor

Endpoint classification committee of two masked clinicians reviewed clinical records of all cardiovascular events reported by recruiting centres to determine whether they met endpoint criteria


Unclear risk

Permanent discontinuation of medication was similar in the ramipril (28.9%) and placebo group (27.3%)


Low risk

No apparent problems

Other bias

Low risk

No apparent problems

INVEST 2003 Methods

Post hoc analysis of the INternational VErapamil-SR/Trandolapril STudy (INVEST). Multicentre, international, randomised, open-label, blinded endpoint study

Participants

Location: 862 centres in 14 countries; patients enrolled September 1997 to February 2003 Inclusion criteria: Patients aged ≥ 50 years with hypertension and clinically stable coronary artery disease [CAD; previous MI, abnormal coronary angiogram (> 50% narrowing of ≥ 1 major coronary artery), abnormalities on 2 different types of stress test or angina pectoris) and a documented history of PAD on the baseline INVEST form. 2699/ 22,576 (12.0%) participants enrolled in the INVEST study had hypertension, stable CAD, and PAD at baseline In the subgroup analysis of patients with concomitant PAD at baseline the following were randomised to receive: Calcium antagonist-based strategy: 1345 participants, mean (SD not reported) age 68. 6 years; 48.2% men; 49.3% white


29

INVEST 2003

(Continued)

Beta-adrenoreceptor blocker-based strategy: 1354 participants, mean (SD not reported) age 68.8 years; 47.6% men; 46.2% white. 2.5% participants in total were lost to followup (no further detail available on these participants) Interventions

Calcium antagonist-based strategy (verapamil SR ± trandolapril) or a beta-adrenoreceptor blocker-based strategy (atenolol ± HCTZ). The first step was either verapamil SR 240 mg daily or atenolol 50 mg daily. Doses could be adjusted downwards if necessary by physician. Other anti-hypertensive drugs were added in stepped fashion to achieve blood pressure control Step 2: verapamil SR/trandolapril 240/2 (4) mg daily or atenolol 50 mg daily plus HCTZ 25 mg daily Step 3: verapamil SR/trandolapril 180/2 (4) mg twice daily or atenolol 50 mg twice daily plus HCTZ 25 mg twice daily Step 4: verapamil SR/trandolapril 180/2 (4) mg twice daily plus HCTZ 25 mg daily or atenolol 50 mg twice daily plus HCTZ 25 mg twice daily plus trandolapril 2 (4) mg daily Step 5: any other non-study anti-hypertensive drug (except beta-adrenoreceptor blockers for calcium antagonist-based strategy patients and calcium antagonists for beta-adrenoreceptor blocker strategy patients) could be added in if needed Duration of treatment: 24 months

Outcomes

Primary outcome: composite endpoint of the first occurrence of all-cause death, nonfatal MI or stroke by ITT analysis Other outcomes: all-cause mortality, cardiovascular mortality, total MI (fatal plus nonfatal), and total stroke (fatal plus non-fatal) Two additional composite outcomes: an event in the primary outcome or poor/fair QoL at the final visit or an event in the primary outcome or first occurrence of a vascular procedure (carotid endarterectomy/stent, amputation, percutaneous peripheral vascular intervention, or aortic aneurysm resection/repair/stent) during follow-up

Notes

Definition of PAD for patients included in this post hoc analysis was a documented history of PAD on the baseline INVEST form. No detailed information regarding the diagnosis of PAD was available There are no significant baseline differences between the treatment groups for those patients with concomitant PAD but patients with PAD were significantly older and had more co-morbidities at baseline than those without PAD

Risk of bias Bias




Randomised using an electronic system available via the Internet


Randomised using an electronic system available via the Internet and investigator informed electronically of treatment allocation. However treatment was open label

Unclear risk


30

INVEST 2003

(Continued)

Blinding (performance bias and detection High risk bias) Participant

Open-label trial

Blinding (performance bias and detection High risk bias) Physician

Open-label trial. Physicians could down titrate initial dose of verapamil or HCTZ monotherapy or up-titrate in a stepped fashion as detailed in the Intervention section. The final step allowed the physician to add in any non-study anti-hypertensive (except beta-adrenoreceptor blockers for calcium antagonist-based strategy patients and calcium antagonists for betaadrenoreceptor blocker strategy patients) at their discretion to control blood pressure

Blinding (performance bias and detection Low risk bias) Outcome assessor

Outcomes adjudicated by a blinded events committee


Unclear risk

2.5% participants with concomitant PAD were lost to follow-up (no further detail available on these participants)


High risk

Data analysed on the ITT population. In the INVEST protocol and main results papers the individual components of the composite endpoints are given by treatment strategy but only two composite endpoints are reported in the subgroup analysis in PAD patients

Other bias

High risk

Post hoc analysis and therefore the patients were not randomised to treatment on the basis of their PAD diagnosis. Definition of PAD for patients included in this post hoc analysis was a documented history of PAD on the baseline INVEST form. No detailed information regarding the diagnosis of PAD was available

NORMA 2011 Methods

Nebivolol or Metoprolol in Arterial Occlusive Disease (NORMA) Trial (ISRCTN06278310), prospective, randomised, double-blind, single-centre trial


31

NORMA 2011

(Continued)

Participants

Location: single-centre in Germany Inclusion criteria: Patients with stable IC (Fontaine Stage II) for ≥ 6 months and an ABI of < 0.90 were recruited. All patients had stage I arterial hypertension (SBP 140 - 159 mmHg and DBP 90 - 99 mmHg) or a previous diagnosis of stage I arterial hypertension currently under treatment. Men and post-menopausal women were recruited. Previous treatment with nebivolol or carvedilol was not permitted 128 participants randomised to receive nebivolol (n = 65) or metoprolol (n = 63) but endpoint analysis (and demographics) only available on n = 109 (85.2%) Nebivolol group: 52 (13 dropouts); mean (SD) age 66.7 (8.3) years; 45 (86.5%) men Metoprolol group: 57 (6 dropouts); mean (SD) age 65.9 (7.9) years; 41 (71.9%) men

Interventions

Nebivolol 5 mg od or metoprolol 95 mg od. Duration: 48 weeks of treatment

Outcomes

Outcomes not specified as primary and secondary. However, the study was powered to detect a difference in flow-mediated dilatation (FMD) between the groups Outcomes were the change in ABI, IC distance (metres until onset of pain), ACD (distance beyond which exercise could not be continued because of claudication pain), QoL, and endothelial-dependent FMD between baseline and 48 weeks of treatment Although not listed as secondary endpoints the paper also reports on all-cause mortality and revascularisation (number requiring a revascularisation procedure) which are of interest to this Cochrane review

Notes

Only post-menopausal women were recruited (to exclude the effect of female hormones on endothelial function). No significant differences in any baseline characteristics between the two treatment groups; borderline significant difference (P = 0.06) in the number of men in each group (with more men in the nebivolol group) In the data analysis section the study authors state that analyses were performed for two populations: safety population (those who received ≥ 1 dose of double-blind medication) and an endpoint population (all patients for whom the endpoint variables were available) . However, only the endpoint analyses are reported

Risk of bias Bias




No description of how the treatment allocation was generated other than that the patients were randomised


Unclear risk





32

NORMA 2011

(Continued)




Clinical monitoring, data management, and statistical analysis were performed by a company but unclear it the study authors were involved in the outcome assessments


Unclear risk

Authors estimated a 20% dropout rate after screening. Endpoint data were not available on 19 randomised patients. 13 participants randomised to nebivolol dropped out. Six participants randomised to metoprolol dropped out


High risk

The study authors reported on all of the outcomes stated in the methods but although 128 participants were randomised, endpoint analyses were only available on n = 109. In the data analysis section the study authors state that analyses were performed for two populations: safety population (those who received ≥ 1 dose of double-blind medication) and an endpoint population (all patients for whom the endpoint variables were available). However, only the endpoint analyses are reported. Authors state that the study had 80% power to detect a 2.0% change in FMD between the treatment groups, based on their planned sample size of n = 51 in each group

Other bias

Unclear risk

Only post-menopausal women were recruited (to exclude the effect of female hormones on endothelial function). No significant differences in any baseline characteristics between the two treatment groups; borderline significant difference (P = 0.06) in the number of men in each group (with more men in the nebivolol group)


33

Overlack 1994 Methods

Two-centre, randomised, double-blind, placebo-controlled trial Dropout rate: 3.2% in treatment group; 1.7% in placebo group

Participants

Location: two centres supervising five general practices, Germany Inclusion criteria: patients with newly diagnosed or pre-treated essential hypertension, defined as sitting DBP of 95 -104 mmHg and one of nine concomitant diseases or therapies: hyperlipidaemia, type II diabetes mellitus, ischaemic heart disease, cardiac arrhythmias, PAD, nephropathy with proteinuria, chronic obstructive pulmonary disease (COPD), or degenerative joint disease treated with non-steroidal anti-inflammatory drugs (NSAIDS). Subgroup with PAD patients, defined as a history of IC ≥ 6 months, a pain-free walking distance of 80 to 200 m (Fontaine Stage IIb), and angiographic or ultrasound evidence of iliac or femoral occlusion Number of patients: 490 (only 54 with PAD) Males: 263; females: 227 Age: 40-75 years Perindopril group: 253 (26 with PAD) Placebo group: 237 (28 with PAD)

Interventions

Perindopril 4 mg od or placebo Duration: six weeks

Outcomes

PAD patients: Doppler ankle pressures, pain-free and MWD, SBP, DBP and heart rate

Notes Risk of bias Bias






Unclear risk

No description of how treatment allocation was concealed other than that the patients were randomised


No description of how the participant was blinded to treatment allocation other than that the trial was double-blind


No description of how the physician was blinded to treatment allocation other than that the trial was double-blind


Blood pressure readings were measured using an automated device which printed out the values and dated them. These printouts were included with the follow-up records.


34

Overlack 1994

(Continued)

All data analyses were conducted centrally in Munich, Germany using the DataEase system. There was no other description of blinding to the other outcome measures including Doppler index, and claudication and MWD Incomplete outcome data (attrition bias) All outcomes

Unclear risk

There was overall dropout rate of 3.2% and 1.7% in the treatment and placebo groups, respectively, but the actual number of PAD patients with follow-up data was not clear


High risk

The study authors do not report all the data collected for all the various subgroups, just the most disease-specific or relevant outcomes

Other bias

Low risk

All data analyses were conducted centrally in Munich using the DataEase system

Schweizer 1998 Methods

Randomised, placebo-controlled trial. Method of randomisation not mentioned. Dropouts: one from the treatment group; two from the placebo group

Participants

Location: Germany Inclusion criteria: patients with Fontaine Stage IIb (walking distance < 200 m on treadmill at 4 km/h at a 10° gradient) PAD and concomitant chronic stable angina pectoris and mild hypertension plus one other risk factor from undergoing percutaneous transluminal coronary angioplasty (PTCA). PAD was diagnosed based on arterial angiography and colour-coded duplex ultrasound, with occlusions (diameter ≤ 5 cm) or subtotal stenoses in the distal superficial femoral artery present for > 6 months Number of patients: 98 Verapamil group: 49 (1 dropout = 48) Placebo group: 49 (2 dropouts = 47)

Interventions

Verapamil 240 mg twice daily, or placebo Duration: six months

Outcomes

Assessments before, immediately after, and at six weeks and six months from baseline of: the degree of stenosis measured by angiography; superficial femoral artery IMT measured by colour duplex ultrasound; SBP was measured in the arm and posterior tibial artery by means of continuous wave Doppler ultrasound in the PTCA-treated leg - the ankle/brachial SBP ratio was then calculated; distance to claudication; SBP, DBP and ventricular septal thickness

Notes Risk of bias Treatment of hypertension in peripheral arterial disease (Review) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

35

Schweizer 1998

(Continued)

Bias




No description other than being random


Unclear risk

No description of allocation concealment other than in a randomised, double-blind manner


No description of blinding of the participant except for the study being doubleblind


No description of blinding of the physician except for the study being double-blind


The colour-coded duplex scans were reviewed by two independent experts unaware of which group the participant was allocated to


Low risk

One verapamil patient and two placebo patients were placed on other medication during the trial and their data were not included in the analyses


High risk

Distance to claudication after treatment not reported

Other bias

Unclear risk

Measurement of the layer thickness: in separate experiments with three observers and four repeated measures of layer thickness for 36 patients, intra-observer variability was 3.1% and inter-observer variability was 5.9%

Zankl 2010 Methods

Pilot study, single-centre, prospective, single-blind

Participants

Location: single centre at an academic hospital in Germany, recruited April 2004 to February 2006 Inclusion criteria: PAD patients at Fontaine Stage IIa or higher with mild to moderate arterial hypertension, 36 participants (26 men), aged 18-80 years Telmisartan group: 18 (0 dropouts). Median (95% CI) age 57 (53-64) years Placebo group: 18 (0 dropouts). Median (95% CI) age 63 (56-75) years


36

Zankl 2010

(Continued)

Interventions

Telmisartan 40 mg or 80 mg od or placebo. Initial dose of telmisartan was 40 mg od. After 4 weeks of treatment, study medication uptitrated to 80 mg daily if SBP was ≥ 150 mmHg at this visit Duration: 12 months

Outcomes

Primary endpoint: AWD Secondary endpoints: FMD, carotid IMT, ABI, and disease-related QoL

Notes

n = 40 randomised to treatment but only 36 completed the study and were analysed (attrition bias). The four who dropped were out due to premature discontinuation of the study medication, due to non-adherence. No detail is given on which drug they were randomised to. IMT was assessed by more than one sonographer but they were trained using a standardised protocol (not specified in paper) and used a common and extensively validated imaging protocol. A minimum of three measurements at different sites on each common carotid artery were obtained and IMT values were averaged. Power calculation suggests that n = 18 in each arm had 80% power to detect a 1.5% difference in MWD Study supported by Bayer.

Risk of bias Bias






Unclear risk



Single-blind but no description given on blinding


Physician was unaware of treatment allocation but no description of blinding given


No detail is given on the blinding of the outcome assessor


n = 40 randomised to treatment but only 36 completed the study and were analysed. The four dropped out due to premature discontinuation of the study medication due to non-adherence. No detail is given on which drug they were randomised to

Unclear risk


37

Zankl 2010

(Continued)


Unclear risk

All outcomes mentioned in the methods are included in the results. Data not available for the four (10%) participants who dropped out

Other bias

Unclear risk

Baseline differences between the two groups despite randomisation (not reported) but ANCOVA was performed which found no confounding effects of differences in baseline values on treatment. Very small sample size

ABI: ankle brachial index ACD: absolute claudication distance CAD: coronary artery disease COPD: chronic obstructive pulmonary disease DBP: diastolic blood pressure FMD: flow-mediated dilatation HCTZ: hydrochlorothiazide HDL: high-density lipoprotein IC: intermittent claudication IMT: intima-media thickness ITT: intention-to-treat MI: myocardial infarction NSAIDS: non-steroidal anti-inflammatory drugs od: once daily PAD: peripheral arterial disease PTCA: percutaneous transluminal coronary angioplasty PVD: peripheral vascular disease SBP: systolic blood pressure SD: standard deviation QoL: quality of life

Characteristics of excluded studies [ordered by study ID]

Study

Reason for exclusion

ABCD 2003

The data for PAD patients were not available. All patients had concomitant diabetes mellitus

Ahimastos 2006

Patients were not hypertensive at baseline

ASCOT 2005

The data for PAD patients were not available


38

(Continued)

Bernardi 1988

The treatment period for each arm in this trial was two weeks only and the minimum for inclusion is one month

Bogaert 1983

This study fits the inclusion criteria except that the data were presented as a line graph in the results. The author has been successfully contacted but the relevant data are no longer available

Bostrom 1986

Poorly designed study with only seven patients and no clear outcome measure. Attempts to contact the authors have been unsuccessful

Branchereau 1995

The active drug, ifenprodil, is not an anti-hypertensive drug although it blocks alpha1-adrenoreceptors

Brown 1998

This study is of treatment titration and not of outcome

Casiglia 1997

Walking distance data were presented as a line graph and attempts to contact the authors have been unsuccessful

Coto 1989

The active drug in this double-blind, placebo-controlled trial was an antiplatelet drug, not anti-hypertensive medication

Coto 1991

This study was not a randomised controlled trial

Diehm 1993

This study is a randomised controlled trial but the results are confounded by the potential addition of a nitrate to lower blood pressure further

Domschky 1977

The active drug in this study was not an anti-hypertensive medication

Gastmann 1987

Only published as an abstract but the abstract was not available

Hiatt 1985

The treatment period for this trial was two weeks only and the minimum for inclusion is one month

Ingram 1982


Jageneau 1977


Kalus 1995

The treatment in this trial comprised a single dose only, and the minimum for inclusion is one month

Klieber 1986

The treatment period for this trial was only 25 days and the minimum for inclusion is one month

Larsen 1969

This trial did not compare two anti-hypertensive therapies or one therapy against placebo

Laurent 1994

Hypertensive patients were actively excluded from this study

Leeman 1995

This paper was concerned with abdominal aortic aneurysms and not peripheral occlusive disease

Lepantalo 1983

Although this trial measured calf blood flow under treatment with beta-blockers, the patient cohort did not have PAD

Lepantalo 1984

The treatment period for this trial was three weeks only and the minimum for inclusion is one month


39

(Continued)

Lepantalo 1985a

The treatment period for this trial was 10 days only and the minimum for inclusion is one month

Lepantalo 1985b

This is a retrospective case control study and not a randomised controlled study

Liakishev 2008

This is a comment on the results of the ONTARGET trial not an original data paper

Lievre 1996

The drug in this study, beraprost, is not an accepted anti-hypertensive medication

LIFE 2002


Liu 1997

The treatment in this trial comprised only one dose and the minimum for inclusion is one month

Mann 1998

This paper describes a study design only and contains no results

Natali 1989

The treatment period was 10 days only in this study and the minimum for inclusion is one month

Nelson 1978


Novo 1985

This was not a randomised, controlled trial of anti-hypertensive therapy in peripheral vascular disease

Novo 1986

Only one patient in this study was symptomatic of peripheral vascular disease. Attempts to contact the authors have been unsuccessful

Novo 1996

Cross-over trial of captopril against ticlopidine and placebo, never tested against either drug though it was included in a sequence of treatments but at the same time in both treatment groups

ONTARGET 2008


OPERA 2002

PAD patients not included in this study

Panzner 1992

Patients with peripheral vascular disease were not studied

POISE 2008

Wrong disease group. This study included patients with atherosclerotic disease undergoing non-cardiac surgery

Reichert 1975

The treatment period was two weeks only and not the minimum of one month

Roberts 1987

Cross-over trial, with the data from both or all phases presented lumped together, and not analysed separately

Roberts 1992

Cross-over trial with the data from both or all phases presented lumped together, and not separately

Rouffy 1989

Hypertensive patients accounted for 40% of the cohort. The data were not presented for the hypertensive patients alone and thus the study could not be included. Attempts to contact the authors have been unsuccessful

Schweizer 1996

Patients were not hypertensive at the outset of this study

Siniscalchi 1993

The outcome measures in this study did not include any specific for PVD, i.e. walking distance


40

(Continued)

Smith 1982

The treatment period for this trial was two weeks only and the minimum for inclusion is one month

Solomon 1991

This study is of adequate design but the standard deviation was missing from the published data and the authors have failed to respond to requests for further data

Spence 1993

Patients were not hypertensive at the outset of this study

Staessen 1978


Stumpe 1993

This paper included patients with PAD but does not use measurements of PAD as outcome measures

Stumpe 1995

This paper does not contain patients with PVD as a main or subgroup

Sutton-Tyrell 1995

This is a good study of mortality with anti-hypertensive therapy but the therapies were mixed and the paper did not specify which patient was on which dose etc. Also, carotid stenosis and PAD were presented together in the results. Attempts to contact the authors have failed

Svendsen 1986

Cross-over trial, with the data from both or all phases presented lumped together, and not separately

Takeda 2010

This study did not include PAD patients

VALUE 2006


Van de Ven 1994


Weibull 1992

This study did not include PAD patients as a study or subgroup

Winterfeld 1984


PAD: peripheral arterial disease

Characteristics of studies awaiting assessment [ordered by study ID] Ahimastos 2013 Methods

Randomised, double-blind, placebo-controlled trial

Participants

Location: three hospitals in Australia (Melbourne, Townsville and Brisbane), participants recruited between 10 May 2008 and 23 August 2011 Inclusion criteria: ABI < 0.90 at rest in at least one leg; history of IC (unilateral or bilateral) and stable for the previous 6 months; and a stable medication regimen for at least 6 months. Hypertension was NOT one of the inclusion criteria although half (n = 106) the patients were hypertensive at baseline. Patients with resting brachial blood pressure of > 160/100 mmHg were excluded Ramipril group: 106 (7 drop-outs). Mean (SD) age 65.5 (5.3) years; 87 (82.1%) men Placebo group: 106 (5 drop-outs). Mean (SD) age 65.5 (7.1) years; 90 (84.9%) men


41

Ahimastos 2013

(Continued)

Interventions

Ramipril 10 mg od or matching placebo Duration: 24 weeks

Outcomes

Primary outcomes: pain-free walking time (time to onset of claudication pain) and maximum walking time Secondary outcomes: ABI; stenosis severity (duplex ultrasound of lower limb arteries); patient-reported symptoms and functional status (assessed by the Walking Impairment Questionnaire); and health-related QoL

Notes

Randomisation process reported as ’tamper-proof ’, with participants randomised into blocks of 10 to receive ramipril or matching placebo. All investigators, analysts and participants were blinded to drug assignment and baseline data when they performed follow-up measurements. No cross-over. Not all participants were hypertensive at baseline

ABI: ankle brachial index IC: intermittent claudication od: once daily QoL: quality of life


42

DATA AND ANALYSES

Comparison 1. ACE inhibitors versus placebo

Outcome or subgroup title 1 Cardiovascular events 2 Claudication distance 3 Maximum walking distance 4 Ankle brachial pressure index

No. of studies

No. of participants

1 1 1 1

Statistical method Odds Ratio (M-H, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI)

Effect size Totals not selected Totals not selected Totals not selected Totals not selected

Comparison 2. Calcium antagonists versus placebo

Outcome or subgroup title 1 Degree of diameter stenosis 2 Ankle brachial pressure index 3 Arterial intima-media thickness

No. of studies

No. of participants

1 1 1

Statistical method Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI)

Effect size Totals not selected Totals not selected Totals not selected

Comparison 3. Thiazide diuretics versus alpha-adrenoreceptor blocking drugs

Outcome or subgroup title 1 Arterial intima-media thickness (IMT)

No. of studies

No. of participants

1

Statistical method Mean Difference (IV, Fixed, 95% CI)

Effect size Totals not selected

Comparison 4. Angiotensin-II receptor antagonist versus placebo

Outcome or subgroup title 1 Maximum walking distance at 12 months (m) 2 Intima-media thickness at 12 months (cm) 3 Ankle-brachial pressure index

No. of studies

No. of participants

Statistical method

Effect size

Other data

No numeric data

Other data

No numeric data

Other data

No numeric data

Comparison 5. Beta-adrenoreceptor blockers versus thiazide diuretics Treatment of hypertension in peripheral arterial disease (Review) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

43

Outcome or subgroup title 1 Change in intermittent claudication distance 2 Absolute claudication distance 3 Change in ankle brachial pressure index 4 All-cause mortality 5 Non-fatal cardiovascular events

No. of studies

No. of participants

Statistical method

Effect size

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

1 1

Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI)

Totals not selected Totals not selected

1 1

Odds Ratio (M-H, Fixed, 95% CI) Odds Ratio (M-H, Fixed, 95% CI)


Comparison 6. Beta-adrenoreceptor blockers versus beta-adrenoreceptor blockers

Outcome or subgroup title 1 All-cause mortality 2 Ankle brachial pressure index 3 Intermittent claudication distance 4 Absolute claudication distance 5 Need for revascularisation

No. of studies

No. of participants

Statistical method

Effect size

1 1 1

Odds Ratio (M-H, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI)

Totals not selected Totals not selected Totals not selected

1 1

Mean Difference (IV, Fixed, 95% CI) Odds Ratio (M-H, Fixed, 95% CI)


Comparison 7. Calcium antagonist-based strategy versus beta-adrenoreceptor blocker-based strategy

Outcome or subgroup title 1 Composite endpoint of death, non-fatal MI, or non-fatal stroke 2 Composite endpoint of death, non-fatal MI or stroke, and revascularisation

No. of studies

No. of participants

Statistical method

Effect size

1

Risk Ratio (M-H, Fixed, 95% CI)

Totals not selected

1

Risk Ratio (M-H, Fixed, 95% CI)

Totals not selected


44

WHAT’S NEW Last assessed as up-to-date: 19 March 2013.

Date

Event

Description

25 March 2013

New search has been performed

Four new trials included and seven new trials excluded. One study added to ’Studies awaiting classification’

25 March 2013

New citation required but conclusions have not changed Four new studies added to the included studies and seven new trials excluded. One study added to ’Studies awaiting classification’. Conclusions not changed

HISTORY Protocol first published: Issue 2, 2001 Review first published: Issue 4, 2003

Date

Event

Description

1 June 2009

New citation required but conclusions have not Change in authors. changed

1 June 2009

New search has been performed

Two additional trials included and 13 additional trials excluded

30 April 2008

Amended

Converted to new review format.

25 February 2004

Amended

Minor copy edits made.

CONTRIBUTIONS OF AUTHORS DAL updated the review. GYHL identified and checked papers for relevance, and checked and edited the text of the review.


45

DECLARATIONS OF INTEREST DL has declared that she is in receipt of investigator-initiated educational grants from Bayer Healthcare and Boehringer Ingelheim for studies not related to the topic of this review. She has also served on the speakers bureau for Boehringer Ingelheim, Bayer and BMS/ Pfizer and received reimbursement of meeting expenses from Boehringer Ingelheim. GYL has served as a consultant and board member and received meeting expenses from Bayer, Astellas, Merck, AstraZeneca, Sanofi, BMS/Pfizer, Biotronik, Portola and Boehringer Ingelheim; and served on the speakers bureau for Bayer, BMS/Pfizer, Boehringer Ingelheim, and Sanofi-Aventis. GYL has also reported receiving funds for development of educational presentations from Bayer, Merck, Sanofi, and Boehringer Ingelheim.

SOURCES OF SUPPORT Internal sources • Sandwell & West Birmingham Hospitals NHS Trust, UK.

External sources • Chief Scientist Office, Scottish Government Health Directorates, The Scottish Government, UK. The PVD Group editorial base is supported by the Chief Scientist Office

DIFFERENCES BETWEEN PROTOCOL AND REVIEW None

INDEX TERMS Medical Subject Headings (MeSH) Antihypertensive Agents [∗ therapeutic use]; Hypertension [complications; ∗ drug therapy]; Intermittent Claudication [complications; drug therapy]; Peripheral Vascular Diseases [complications; ∗ drug therapy]; Randomized Controlled Trials as Topic

MeSH check words Female; Humans; Male


46

Percutaneous endovascular treatment of peripheral arterial disease in Germany.

Determinants of invasive treatment in lower extremity peripheral arterial disease.

Ticagrelor for the treatment of peripheral arterial disease.

Peripheral arterial disease.

[Treatment of pulmonary arterial hypertension].

Atherectomy for peripheral arterial disease.

Evaluating peripheral arterial occlusive disease.

Therapeutic ultrasound plus pulsed electromagnetic field improves recovery from peripheral arterial disease in hypertension.

Arterial stiffness in patients with peripheral arterial disease.

Reply to arterial stiffness in patients with peripheral arterial disease.

Bioresorbable scaffolds in peripheral arterial disease.

Antithrombotic therapy in peripheral arterial occlusive disease.

[Innovative therapies in arterial hypertension treatment].

Spatiotemporal Changes Posttreatment in Peripheral Arterial Disease.

Advances in peripheral arterial disease endovascular revascularization.

Below-knee amputation in peripheral arterial disease.

Treatment differences in pulmonary arterial hypertension management.

Peripheral blood signature of vasodilator-responsive pulmonary arterial hypertension.

Laser angioplasty of peripheral arterial occlusive disease.

Updated treatment algorithm of pulmonary arterial hypertension.

Patients with resistant hypertension have more peripheral arterial disease than other uncontrolled hypertensives.

pulmonary arterial hypertension in congenital heart disease and therapy of pulmonary arterial hypertension in children].

A review of the role of anticoagulation in the treatment of peripheral arterial disease.

[Antithrombotic treatment after peripheral arterial surgery].