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Le traitement de l'hypertension dans la maladie artérielle périphérique

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Referencias

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HOPE 2004 {published and unpublished data}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, Cooper‐DeHoff 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.

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.

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 non‐insulin‐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 Anglo‐Scandinavian 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 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 beta‐adrenergic‐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 beta‐blockade 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 peripheral arterial occlusive disease. Vascular Medicine 1997;2(1):13‐8.

Mann 1998 {published data only}

Mann J, Julius S. The Valsartan Antihypertensive Long‐term 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.

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, Morris‐Jones 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 Long‐term 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 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.

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, Cooper‐DeHoff 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 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, 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, 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]

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 double‐blind 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 three‐years 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 bias)

Unclear risk

No description given, only that patients were randomised

Allocation concealment (selection bias)

Unclear risk

No description given, only that patients were randomised

Blinding (performance bias and detection bias)
Participant

Unclear risk

Trial described as double‐blind but no description given

Blinding (performance bias and detection bias)
Physician

Unclear risk

Trial described as double‐blind but no description given

Blinding (performance bias and detection bias)
Outcome assessor

Unclear risk

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 inter‐observer 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
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

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomised 1:1 using a computer‐generated randomisation list

Allocation concealment (selection bias)

Low risk

Randomised 1:1 using a computer‐generated randomisation list

Blinding (performance bias and detection bias)
Participant

Low risk

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 bias)
Physician

Low risk

Double‐blind trial, tablets identical in appearance and allocation done by computer‐generated randomisation list

Blinding (performance bias and detection bias)
Outcome assessor

Unclear risk

No detail given on the blinding of the outcome assessors

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

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

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomised using a central telephone service

Allocation concealment (selection bias)

Low risk

Randomised using a central telephone service

Blinding (performance bias and detection bias)
Participant

Low risk

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

Blinding (performance bias and detection bias)
Physician

Low risk

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

Blinding (performance bias and detection bias)
Outcome assessor

Low risk

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

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

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

Selective reporting (reporting bias)

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

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 follow‐up (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, non‐fatal MI or stroke by ITT analysis

Other outcomes: all‐cause mortality, cardiovascular mortality, total MI (fatal plus non‐fatal), 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

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomised using an electronic system available via the Internet

Allocation concealment (selection bias)

Unclear risk

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

Blinding (performance bias and detection bias)
Participant

High risk

Open‐label trial

Blinding (performance bias and detection bias)
Physician

High risk

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 beta‐adrenoreceptor blocker strategy patients) at their discretion to control blood pressure

Blinding (performance bias and detection bias)
Outcome assessor

Low risk

Outcomes adjudicated by a blinded events committee

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

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

Selective reporting (reporting bias)

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

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

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

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

Allocation concealment (selection bias)

Unclear risk

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

Blinding (performance bias and detection bias)
Participant

Unclear risk

Trial described as double‐blind but no description given

Blinding (performance bias and detection bias)
Physician

Unclear risk

Trial described as double‐blind but no description given

Blinding (performance bias and detection bias)
Outcome assessor

Unclear risk

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

Incomplete outcome data (attrition bias)
All outcomes

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

Selective reporting (reporting bias)

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)

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

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

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

Allocation concealment (selection bias)

Unclear risk

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

Blinding (performance bias and detection bias)
Participant

Unclear risk

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

Blinding (performance bias and detection bias)
Physician

Unclear risk

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

Blinding (performance bias and detection bias)
Outcome assessor

Unclear risk

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. 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

Selective reporting (reporting bias)

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

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

No description other than being random

Allocation concealment (selection bias)

Unclear risk

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

Blinding (performance bias and detection bias)
Participant

Unclear risk

No description of blinding of the participant except for the study being double‐blind

Blinding (performance bias and detection bias)
Physician

Unclear risk

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

Blinding (performance bias and detection bias)
Outcome assessor

Unclear risk

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

Incomplete outcome data (attrition bias)
All outcomes

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

Selective reporting (reporting bias)

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

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

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

No description given, only that patients were randomised

Allocation concealment (selection bias)

Unclear risk

No description given, only that patients were randomised

Blinding (performance bias and detection bias)
Participant

Unclear risk

Single‐blind but no description given on blinding

Blinding (performance bias and detection bias)
Physician

Unclear risk

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

Blinding (performance bias and detection bias)
Outcome assessor

Unclear risk

No detail is given on the blinding of the outcome assessor

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

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

Selective reporting (reporting bias)

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

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

This study was not a randomised controlled trial

Jageneau 1977

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

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

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

The data for PAD patients were not available

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

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

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

The data for PAD patients were not available

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

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

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

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

The data for PAD patients were not available

Van de Ven 1994

This study was not a randomised controlled trial

Weibull 1992

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

Winterfeld 1984

This study was not a randomised controlled trial

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

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

Data and analyses

Open in table viewer
Comparison 1. ACE inhibitors versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Cardiovascular events Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

Analysis 1.1

Comparison 1 ACE inhibitors versus placebo, Outcome 1 Cardiovascular events.

Comparison 1 ACE inhibitors versus placebo, Outcome 1 Cardiovascular events.

2 Claudication distance Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

Analysis 1.2

Comparison 1 ACE inhibitors versus placebo, Outcome 2 Claudication distance.

Comparison 1 ACE inhibitors versus placebo, Outcome 2 Claudication distance.

3 Maximum walking distance Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

Analysis 1.3

Comparison 1 ACE inhibitors versus placebo, Outcome 3 Maximum walking distance.

Comparison 1 ACE inhibitors versus placebo, Outcome 3 Maximum walking distance.

4 Ankle brachial pressure index Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

Analysis 1.4

Comparison 1 ACE inhibitors versus placebo, Outcome 4 Ankle brachial pressure index.

Comparison 1 ACE inhibitors versus placebo, Outcome 4 Ankle brachial pressure index.

Open in table viewer
Comparison 2. Calcium antagonists versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Degree of diameter stenosis Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

Analysis 2.1

Comparison 2 Calcium antagonists versus placebo, Outcome 1 Degree of diameter stenosis.

Comparison 2 Calcium antagonists versus placebo, Outcome 1 Degree of diameter stenosis.

2 Ankle brachial pressure index Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

Analysis 2.2

Comparison 2 Calcium antagonists versus placebo, Outcome 2 Ankle brachial pressure index.

Comparison 2 Calcium antagonists versus placebo, Outcome 2 Ankle brachial pressure index.

3 Arterial intima‐media thickness Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

Analysis 2.3

Comparison 2 Calcium antagonists versus placebo, Outcome 3 Arterial intima‐media thickness.

Comparison 2 Calcium antagonists versus placebo, Outcome 3 Arterial intima‐media thickness.

Open in table viewer
Comparison 3. Thiazide diuretics versus alpha‐adrenoreceptor blocking drugs

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Arterial intima‐media thickness (IMT) Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

Analysis 3.1

Comparison 3 Thiazide diuretics versus alpha‐adrenoreceptor blocking drugs, Outcome 1 Arterial intima‐media thickness (IMT).

Comparison 3 Thiazide diuretics versus alpha‐adrenoreceptor blocking drugs, Outcome 1 Arterial intima‐media thickness (IMT).

Open in table viewer
Comparison 4. Angiotensin‐II receptor antagonist versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Maximum walking distance at 12 months (m) Show forest plot

Other data

No numeric data

Analysis 4.1

Study

Telmisartan (n = 18)

Placebo (n = 18)

Zankl 2010

Median (95% CI)

Median (95% CI)

Zankl 2010

191 (157 ‐ 226)

132 (103 ‐ 192)



Comparison 4 Angiotensin‐II receptor antagonist versus placebo, Outcome 1 Maximum walking distance at 12 months (m).

2 Intima‐media thickness at 12 months (cm) Show forest plot

Other data

No numeric data

Analysis 4.2

Study

Telmisartan (n = 18)

Placebo (n = 18)

Zankl 2010

Median (95% CI)

Median (95% CI)

Zankl 2010

0.08 (0.07 ‐ 0.09)

0.09 (0.08 ‐ 1.00)



Comparison 4 Angiotensin‐II receptor antagonist versus placebo, Outcome 2 Intima‐media thickness at 12 months (cm).

3 Ankle‐brachial pressure index Show forest plot

Other data

No numeric data

Analysis 4.3

Study

Telmisartan (n = 18)

Placebo (n = 18)

Zankl 2010

Median (95% CI)

Median (95% CI)

Zankl 2010

0.60 (0.60 ‐ 0.77)

0.52 (0.48 ‐ 0.67)



Comparison 4 Angiotensin‐II receptor antagonist versus placebo, Outcome 3 Ankle‐brachial pressure index.

Open in table viewer
Comparison 5. Beta‐adrenoreceptor blockers versus thiazide diuretics

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Change in intermittent claudication distance Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

Analysis 5.1

Comparison 5 Beta‐adrenoreceptor blockers versus thiazide diuretics, Outcome 1 Change in intermittent claudication distance.

Comparison 5 Beta‐adrenoreceptor blockers versus thiazide diuretics, Outcome 1 Change in intermittent claudication distance.

2 Absolute claudication distance Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

Analysis 5.2

Comparison 5 Beta‐adrenoreceptor blockers versus thiazide diuretics, Outcome 2 Absolute claudication distance.

Comparison 5 Beta‐adrenoreceptor blockers versus thiazide diuretics, Outcome 2 Absolute claudication distance.

3 Change in ankle brachial pressure index Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

Analysis 5.3

Comparison 5 Beta‐adrenoreceptor blockers versus thiazide diuretics, Outcome 3 Change in ankle brachial pressure index.

Comparison 5 Beta‐adrenoreceptor blockers versus thiazide diuretics, Outcome 3 Change in ankle brachial pressure index.

4 All‐cause mortality Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

Analysis 5.4

Comparison 5 Beta‐adrenoreceptor blockers versus thiazide diuretics, Outcome 4 All‐cause mortality.

Comparison 5 Beta‐adrenoreceptor blockers versus thiazide diuretics, Outcome 4 All‐cause mortality.

5 Non‐fatal cardiovascular events Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

Analysis 5.5

Comparison 5 Beta‐adrenoreceptor blockers versus thiazide diuretics, Outcome 5 Non‐fatal cardiovascular events.

Comparison 5 Beta‐adrenoreceptor blockers versus thiazide diuretics, Outcome 5 Non‐fatal cardiovascular events.

Open in table viewer
Comparison 6. Beta‐adrenoreceptor blockers versus beta‐adrenoreceptor blockers

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 All‐cause mortality Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

Analysis 6.1

Comparison 6 Beta‐adrenoreceptor blockers versus beta‐adrenoreceptor blockers, Outcome 1 All‐cause mortality.

Comparison 6 Beta‐adrenoreceptor blockers versus beta‐adrenoreceptor blockers, Outcome 1 All‐cause mortality.

2 Ankle brachial pressure index Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

Analysis 6.2

Comparison 6 Beta‐adrenoreceptor blockers versus beta‐adrenoreceptor blockers, Outcome 2 Ankle brachial pressure index.

Comparison 6 Beta‐adrenoreceptor blockers versus beta‐adrenoreceptor blockers, Outcome 2 Ankle brachial pressure index.

3 Intermittent claudication distance Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

Analysis 6.3

Comparison 6 Beta‐adrenoreceptor blockers versus beta‐adrenoreceptor blockers, Outcome 3 Intermittent claudication distance.

Comparison 6 Beta‐adrenoreceptor blockers versus beta‐adrenoreceptor blockers, Outcome 3 Intermittent claudication distance.

4 Absolute claudication distance Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

Analysis 6.4

Comparison 6 Beta‐adrenoreceptor blockers versus beta‐adrenoreceptor blockers, Outcome 4 Absolute claudication distance.

Comparison 6 Beta‐adrenoreceptor blockers versus beta‐adrenoreceptor blockers, Outcome 4 Absolute claudication distance.

5 Need for revascularisation Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

Analysis 6.5

Comparison 6 Beta‐adrenoreceptor blockers versus beta‐adrenoreceptor blockers, Outcome 5 Need for revascularisation.

Comparison 6 Beta‐adrenoreceptor blockers versus beta‐adrenoreceptor blockers, Outcome 5 Need for revascularisation.

Open in table viewer
Comparison 7. Calcium antagonist‐based strategy versus beta‐adrenoreceptor blocker‐based strategy

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Composite endpoint of death, non‐fatal MI, or non‐fatal stroke Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

Analysis 7.1

Comparison 7 Calcium antagonist‐based strategy versus beta‐adrenoreceptor blocker‐based strategy, Outcome 1 Composite endpoint of death, non‐fatal MI, or non‐fatal stroke.

Comparison 7 Calcium antagonist‐based strategy versus beta‐adrenoreceptor blocker‐based strategy, Outcome 1 Composite endpoint of death, non‐fatal MI, or non‐fatal stroke.

2 Composite endpoint of death, non‐fatal MI or stroke, and revascularisation Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

Analysis 7.2

Comparison 7 Calcium antagonist‐based strategy versus beta‐adrenoreceptor blocker‐based strategy, Outcome 2 Composite endpoint of death, non‐fatal MI or stroke, and revascularisation.

Comparison 7 Calcium antagonist‐based strategy versus beta‐adrenoreceptor blocker‐based strategy, Outcome 2 Composite endpoint of death, non‐fatal MI or stroke, and revascularisation.

Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
Figuras y tablas -
Figure 1

Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
Figuras y tablas -
Figure 2

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

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

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

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

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

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

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

Forest plot of comparison: 2 Calcium antagonists versus placebo, outcome: 2.3 Arterial intima‐media thickness.
Figuras y tablas -
Figure 6

Forest plot of comparison: 2 Calcium antagonists versus placebo, outcome: 2.3 Arterial intima‐media thickness.

Comparison 1 ACE inhibitors versus placebo, Outcome 1 Cardiovascular events.
Figuras y tablas -
Analysis 1.1

Comparison 1 ACE inhibitors versus placebo, Outcome 1 Cardiovascular events.

Comparison 1 ACE inhibitors versus placebo, Outcome 2 Claudication distance.
Figuras y tablas -
Analysis 1.2

Comparison 1 ACE inhibitors versus placebo, Outcome 2 Claudication distance.

Comparison 1 ACE inhibitors versus placebo, Outcome 3 Maximum walking distance.
Figuras y tablas -
Analysis 1.3

Comparison 1 ACE inhibitors versus placebo, Outcome 3 Maximum walking distance.

Comparison 1 ACE inhibitors versus placebo, Outcome 4 Ankle brachial pressure index.
Figuras y tablas -
Analysis 1.4

Comparison 1 ACE inhibitors versus placebo, Outcome 4 Ankle brachial pressure index.

Comparison 2 Calcium antagonists versus placebo, Outcome 1 Degree of diameter stenosis.
Figuras y tablas -
Analysis 2.1

Comparison 2 Calcium antagonists versus placebo, Outcome 1 Degree of diameter stenosis.

Comparison 2 Calcium antagonists versus placebo, Outcome 2 Ankle brachial pressure index.
Figuras y tablas -
Analysis 2.2

Comparison 2 Calcium antagonists versus placebo, Outcome 2 Ankle brachial pressure index.

Comparison 2 Calcium antagonists versus placebo, Outcome 3 Arterial intima‐media thickness.
Figuras y tablas -
Analysis 2.3

Comparison 2 Calcium antagonists versus placebo, Outcome 3 Arterial intima‐media thickness.

Comparison 3 Thiazide diuretics versus alpha‐adrenoreceptor blocking drugs, Outcome 1 Arterial intima‐media thickness (IMT).
Figuras y tablas -
Analysis 3.1

Comparison 3 Thiazide diuretics versus alpha‐adrenoreceptor blocking drugs, Outcome 1 Arterial intima‐media thickness (IMT).

Study

Telmisartan (n = 18)

Placebo (n = 18)

Zankl 2010

Median (95% CI)

Median (95% CI)

Zankl 2010

191 (157 ‐ 226)

132 (103 ‐ 192)

Figuras y tablas -
Analysis 4.1

Comparison 4 Angiotensin‐II receptor antagonist versus placebo, Outcome 1 Maximum walking distance at 12 months (m).

Study

Telmisartan (n = 18)

Placebo (n = 18)

Zankl 2010

Median (95% CI)

Median (95% CI)

Zankl 2010

0.08 (0.07 ‐ 0.09)

0.09 (0.08 ‐ 1.00)

Figuras y tablas -
Analysis 4.2

Comparison 4 Angiotensin‐II receptor antagonist versus placebo, Outcome 2 Intima‐media thickness at 12 months (cm).

Study

Telmisartan (n = 18)

Placebo (n = 18)

Zankl 2010

Median (95% CI)

Median (95% CI)

Zankl 2010

0.60 (0.60 ‐ 0.77)

0.52 (0.48 ‐ 0.67)

Figuras y tablas -
Analysis 4.3

Comparison 4 Angiotensin‐II receptor antagonist versus placebo, Outcome 3 Ankle‐brachial pressure index.

Comparison 5 Beta‐adrenoreceptor blockers versus thiazide diuretics, Outcome 1 Change in intermittent claudication distance.
Figuras y tablas -
Analysis 5.1

Comparison 5 Beta‐adrenoreceptor blockers versus thiazide diuretics, Outcome 1 Change in intermittent claudication distance.

Comparison 5 Beta‐adrenoreceptor blockers versus thiazide diuretics, Outcome 2 Absolute claudication distance.
Figuras y tablas -
Analysis 5.2

Comparison 5 Beta‐adrenoreceptor blockers versus thiazide diuretics, Outcome 2 Absolute claudication distance.

Comparison 5 Beta‐adrenoreceptor blockers versus thiazide diuretics, Outcome 3 Change in ankle brachial pressure index.
Figuras y tablas -
Analysis 5.3

Comparison 5 Beta‐adrenoreceptor blockers versus thiazide diuretics, Outcome 3 Change in ankle brachial pressure index.

Comparison 5 Beta‐adrenoreceptor blockers versus thiazide diuretics, Outcome 4 All‐cause mortality.
Figuras y tablas -
Analysis 5.4

Comparison 5 Beta‐adrenoreceptor blockers versus thiazide diuretics, Outcome 4 All‐cause mortality.

Comparison 5 Beta‐adrenoreceptor blockers versus thiazide diuretics, Outcome 5 Non‐fatal cardiovascular events.
Figuras y tablas -
Analysis 5.5

Comparison 5 Beta‐adrenoreceptor blockers versus thiazide diuretics, Outcome 5 Non‐fatal cardiovascular events.

Comparison 6 Beta‐adrenoreceptor blockers versus beta‐adrenoreceptor blockers, Outcome 1 All‐cause mortality.
Figuras y tablas -
Analysis 6.1

Comparison 6 Beta‐adrenoreceptor blockers versus beta‐adrenoreceptor blockers, Outcome 1 All‐cause mortality.

Comparison 6 Beta‐adrenoreceptor blockers versus beta‐adrenoreceptor blockers, Outcome 2 Ankle brachial pressure index.
Figuras y tablas -
Analysis 6.2

Comparison 6 Beta‐adrenoreceptor blockers versus beta‐adrenoreceptor blockers, Outcome 2 Ankle brachial pressure index.

Comparison 6 Beta‐adrenoreceptor blockers versus beta‐adrenoreceptor blockers, Outcome 3 Intermittent claudication distance.
Figuras y tablas -
Analysis 6.3

Comparison 6 Beta‐adrenoreceptor blockers versus beta‐adrenoreceptor blockers, Outcome 3 Intermittent claudication distance.

Comparison 6 Beta‐adrenoreceptor blockers versus beta‐adrenoreceptor blockers, Outcome 4 Absolute claudication distance.
Figuras y tablas -
Analysis 6.4

Comparison 6 Beta‐adrenoreceptor blockers versus beta‐adrenoreceptor blockers, Outcome 4 Absolute claudication distance.

Comparison 6 Beta‐adrenoreceptor blockers versus beta‐adrenoreceptor blockers, Outcome 5 Need for revascularisation.
Figuras y tablas -
Analysis 6.5

Comparison 6 Beta‐adrenoreceptor blockers versus beta‐adrenoreceptor blockers, Outcome 5 Need for revascularisation.

Comparison 7 Calcium antagonist‐based strategy versus beta‐adrenoreceptor blocker‐based strategy, Outcome 1 Composite endpoint of death, non‐fatal MI, or non‐fatal stroke.
Figuras y tablas -
Analysis 7.1

Comparison 7 Calcium antagonist‐based strategy versus beta‐adrenoreceptor blocker‐based strategy, Outcome 1 Composite endpoint of death, non‐fatal MI, or non‐fatal stroke.

Comparison 7 Calcium antagonist‐based strategy versus beta‐adrenoreceptor blocker‐based strategy, Outcome 2 Composite endpoint of death, non‐fatal MI or stroke, and revascularisation.
Figuras y tablas -
Analysis 7.2

Comparison 7 Calcium antagonist‐based strategy versus beta‐adrenoreceptor blocker‐based strategy, Outcome 2 Composite endpoint of death, non‐fatal MI or stroke, and revascularisation.

Comparison 1. ACE inhibitors versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Cardiovascular events Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

2 Claudication distance Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

3 Maximum walking distance Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

4 Ankle brachial pressure index Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

Figuras y tablas -
Comparison 1. ACE inhibitors versus placebo
Comparison 2. Calcium antagonists versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Degree of diameter stenosis Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

2 Ankle brachial pressure index Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

3 Arterial intima‐media thickness Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

Figuras y tablas -
Comparison 2. Calcium antagonists versus placebo
Comparison 3. Thiazide diuretics versus alpha‐adrenoreceptor blocking drugs

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Arterial intima‐media thickness (IMT) Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

Figuras y tablas -
Comparison 3. Thiazide diuretics versus alpha‐adrenoreceptor blocking drugs
Comparison 4. Angiotensin‐II receptor antagonist versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Maximum walking distance at 12 months (m) Show forest plot

Other data

No numeric data

2 Intima‐media thickness at 12 months (cm) Show forest plot

Other data

No numeric data

3 Ankle‐brachial pressure index Show forest plot

Other data

No numeric data

Figuras y tablas -
Comparison 4. Angiotensin‐II receptor antagonist versus placebo
Comparison 5. Beta‐adrenoreceptor blockers versus thiazide diuretics

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Change in intermittent claudication distance Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

2 Absolute claudication distance Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

3 Change in ankle brachial pressure index Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

4 All‐cause mortality Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

5 Non‐fatal cardiovascular events Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

Figuras y tablas -
Comparison 5. Beta‐adrenoreceptor blockers versus thiazide diuretics
Comparison 6. Beta‐adrenoreceptor blockers versus beta‐adrenoreceptor blockers

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 All‐cause mortality Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

2 Ankle brachial pressure index Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

3 Intermittent claudication distance Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

4 Absolute claudication distance Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

5 Need for revascularisation Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

Figuras y tablas -
Comparison 6. Beta‐adrenoreceptor blockers versus beta‐adrenoreceptor blockers
Comparison 7. Calcium antagonist‐based strategy versus beta‐adrenoreceptor blocker‐based strategy

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Composite endpoint of death, non‐fatal MI, or non‐fatal stroke Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

2 Composite endpoint of death, non‐fatal MI or stroke, and revascularisation Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

Figuras y tablas -
Comparison 7. Calcium antagonist‐based strategy versus beta‐adrenoreceptor blocker‐based strategy