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• W1984037141 abstract "Since the terms ‘hypertension’ and ‘microalbuminuria’ were first defined, data from numerous studies have documented the continuous, rather than dichotomous, relation between blood pressure, albumin excretion, and cardiovascular disease. Lower blood pressures, down to at least 115/75 mmHg, and lower albumin excretions, below an estimated 2 mg/day, are associated with less cardiovascular risk. We hypothesize that the abundances of modern civilization superimposed on the Paleolithic genotype of humans, which has not substantially changed in the last 10 000 years, have considerably shifted the ‘normal’ values for blood pressure and various biochemical indices such as albuminuria still found in today's stone-aged cultures to the ‘neo-normal’ values observed today in the rest of the modern world. Defining a large portion of the population as ‘normal’ based upon these dichotomous ‘neo-normal’ standards is not supported by the data, and therefore seems unjustifiable. We propose that the medical community consider abandoning the terms ‘hypertension’ and ‘microalbuminuria’ in favor of ‘blood pressure-associated’ and ‘albuminuria-associated’ disease. Since the terms ‘hypertension’ and ‘microalbuminuria’ were first defined, data from numerous studies have documented the continuous, rather than dichotomous, relation between blood pressure, albumin excretion, and cardiovascular disease. Lower blood pressures, down to at least 115/75 mmHg, and lower albumin excretions, below an estimated 2 mg/day, are associated with less cardiovascular risk. We hypothesize that the abundances of modern civilization superimposed on the Paleolithic genotype of humans, which has not substantially changed in the last 10 000 years, have considerably shifted the ‘normal’ values for blood pressure and various biochemical indices such as albuminuria still found in today's stone-aged cultures to the ‘neo-normal’ values observed today in the rest of the modern world. Defining a large portion of the population as ‘normal’ based upon these dichotomous ‘neo-normal’ standards is not supported by the data, and therefore seems unjustifiable. We propose that the medical community consider abandoning the terms ‘hypertension’ and ‘microalbuminuria’ in favor of ‘blood pressure-associated’ and ‘albuminuria-associated’ disease. The terms ‘hypertension’ and ‘microalbuminuria’ imply a threshold level for blood pressure and albuminuria below which disease risk is not seen. This terminology defines a large group of people as normal, and ignores the impact that even minor variations of blood pressure and albumin excretion may have on disease within the so-called normal range. In this article, we propose that the medical community consider abandoning these terms, discuss blood pressure- and albuminuria-related disease risk, and review treatment targets for associated cardiovascular and renal protection. Following the first measurement of blood pressure in the femoral artery of a horse by Hales in 1733, and the recognition by Bright in 1827 that arteriosclerosis, shrunken and fibrotic kidneys, and cardiac hypertrophy were clinically linked, elevated blood pressure as a distinct entity was initially championed by T Clifford Allbutt in 1893, who was also the first to use the word ‘hyperpiesia’, or hypertension. Early pharmaceuticals were first used to treat malignant hypertension in the 1940s and 1950s, with significant improvements in outcomes. However, whether ‘essential’ hypertension (a term coined by Janeway in 1904) was a benign condition or one that would benefit from treatment was not answered until the VA Cooperative Studies published in 1967 and 1970. Subsequently, the National High Blood Pressure Education Program, developed in 1972 by the National Heart, Lung, and Blood Institute, published the very first report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC 1) in 1977.1.Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. A cooperative study.JAMA. 1977; 237: 255-261Google Scholar This report, whose bibliography included solely the VA study published seven years earlier, recommended intervention in patients with diastolic blood pressures (DBPs) greater than or equal to 90 mmHg; DBP>104 mmHg warranted drug therapy, whereas DBP 90–104 mmHg could initially be approached with risk factor reduction. Although the 1980 guidelines (JNC 2) defined mild, moderate, and severe hypertension along the same cutoffs of DBP, JNC 3 in 1984 included systolic blood pressure (SBP) (‘normal’ SBP being <140 mmHg) in the definition.2.The 1980 Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure.Arch Intern Med. 1980; 140: 1280-1285Google Scholar, 3.The 1984 Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure.Arch Intern Med. 1984; 144: 1045-1057Google Scholar Subsequent JNC guidelines in 1988, 1993, and 1997 adhered to the same definition of ‘normal’ blood pressure, with the recognition by JNC 5 of a ‘high normal’ category, and by JNC 6 of an ‘optimal’ category within the normal range.4.The 1988 Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure.Arch Intern Med. 1988; 148: 1023-1038Google Scholar, 5.The Fifth Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC V).Arch Intern Med. 1993; 153: 154-183Google Scholar, 6.The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.Arch Intern Med. 1997; 157: 2413-2446Google Scholar The seventh report of the JNC recognized the associations between even small increments above 115/75 mmHg with cardiovascular outcomes, retreating somewhat from older definitions by reclassifying the ‘high normal’ group as ‘prehypertension’ instead.7.Chobanian A.V. Bakris G.L. Black H.R. et al.The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report.JAMA. 2003; 289: 2560-2572Google Scholar Based upon the fourth National Health and Nutrition Examination Survey (1999–2000 NHANES), an estimated 58% – the majority of all adults in the United States – have abnormal blood pressure as defined by JNC 7 categories of prehypertension or hypertension.8.Wang Y. Wang Q.J. The prevalence of prehypertension and hypertension among US adults according to the new joint national committee guidelines: new challenges of the old problem.Arch Intern Med. 2004; 164: 2126-2134Google Scholar Given the continuous association between blood pressure and risk as well as the absence of the J-curve, future progressive redefining of normality is all but assured, thus making the term ‘hypertension’ – a term which implies dichotomy – seem unjustifiable. The term ‘microalbuminuria’ first appeared in the medical literature in 1981, used by Viberti and colleagues and Svendsen and colleagues to describe the presence of albuminuria below the detection limit of a standard dipstick, but at a level that was highly predictive of future overt proteinuria in diabetic patients.9.Viberti G. Pickup J.C. Bilous R.W. et al.Correction of exercise-induced microalbuminuria in insulin-dependent diabetics after 3 weeks of subcutaneous insulin infusion.Diabetes. 1981; 30: 818-823Google Scholar, 10.Viberti G.C. Hill R.D. Jarrett R.J. et al.Microalbuminuria as a predictor of clinical nephropathy in insulin-dependent diabetes mellitus.Lancet. 1982; 1: 1430-1432Google Scholar, 11.Svendsen P.A. Oxenboll B. Christiansen J.S. Microalbuminuria in diabetic patients – a longitudinal study.Acta Endocrinol Suppl (Copenhagen). 1981; 242: 53-54Google Scholar Microalbuminuria became an official part of the medical lexicon in 1985, defined as an albumin excretion rate between 20 and 200 μg/min. Although the lower bound was chosen because 95% of ‘normal’ individuals had excretion rates below that limit, it was recognized that risk of progression to nephropathy was elevated among diabetics in the ‘high normal’ range.12.Mathiesen E.R. Ronn B. Jensen T. et al.Relationship between blood pressure and urinary albumin excretion in development of microalbuminuria.Diabetes. 1990; 39: 245-249Google Scholar Similar to the relationship between blood pressure and risk of cardiovascular events, mounting evidence indicates a continuous relationship between albumin excretion and risk. And like blood pressure, the concept of a threshold level to define normality is inconsistent with epidemiological data. The anthropologic record indicates that before the last 5000 to 10 000 years, Homo sapiens was considerably smaller in stature and body weight,13.Morwood M.J. Brown P. Jatmiko et al.Further evidence for small-bodied hominins from the Late Pleistocene of Flores, Indonesia.Nature. 2005; 437: 1012-1017Google Scholar and presumably characterized by lower blood pressure, glomerular filtration rate, and cholesterol than are commonplace today. Stone-age tribes studied today confirm the anthropomorphic and biochemical patterns predicted for earlier humans.14.Oliver W.J. Cohen E.L. Neel J.V. Blood pressure, sodium intake, and sodium related hormones in the Yanomamo Indians, a ‘no-salt’ culture.Circulation. 1975; 52: 146-151Google Scholar, 15.Lowenstein F.M. A study of blood pressure and body measurements in medical students in the Brazilian Amazon City Belem.Cardiologia. 1961; 39: 46-56Google Scholar, 16.Whyte H.M. Yee I.L. Serum cholesterol levels of Australians and natives of New Guinea from birth to adulthood.Australas Ann Med. 1958; 7: 336-339Google Scholar, 17.Whyte H.M. Graham I.A. De Wolfe M.S. Body fat, blood pressure and serum cholesterol of Australian men.Australas Ann Med. 1958; 7: 328-335Google Scholar, 18.De Wolfe M.S. Whyte H.M. Serum cholesterol and lipoproteins in natives of New Guinea and Australians.Australas Ann Med. 1958; 7: 47-54Google Scholar, 19.Whyte H.M. Body fat and blood pressure of natives in New Guinea: reflections on essential hypertension.Australas Ann Med. 1958; 7: 36-46Google Scholar, 20.Casley-Smith J.R. Blood pressures in Australian aborigines.Med J Aust. 1959; 46: 627-633Google Scholar, 21.Maddocks I. Blood pressures in Melanesians.Med J Aust. 1967; 1: 1123-1126Google Scholar, 22.Fleming-Moran M. Santos R.V. Coimbra Junior C.E. Blood pressure levels of the Surui and Zoro Indians of the Brazilian Amazon: group- and sex-specific effects resulting from body composition, health status, and age.Hum Biol. 1991; 63: 835-861Google Scholar, 23.Ghesquiere J.L. Karvonen M.J. Some anthropometric and functional dimensions of the pygmy (Kivu Twa).Ann Hum Biol. 1981; 8: 119-134Google Scholar, 24.Hollenberg N.K. Martinez G. McCullough M. et al.Aging, acculturation, salt intake, and hypertension in the Kuna of Panama.Hypertension. 1997; 29: 171-176Google Scholar At the start of the Holocene 10 000 years ago, the earth's climate warmed, allowing people to establish villages and invent the basic tools of agriculture, herding, and metallurgy. Humans began to grow considerably in stature and body mass, and our ‘paleo-normal’ physiologic values, perhaps lower than 90 mmHg for SBP, 100 mg/dl for total serum cholesterol, increased substantially to our current ‘neo-normal’ base of reference.14.Oliver W.J. Cohen E.L. Neel J.V. Blood pressure, sodium intake, and sodium related hormones in the Yanomamo Indians, a ‘no-salt’ culture.Circulation. 1975; 52: 146-151Google Scholar, 16.Whyte H.M. Yee I.L. Serum cholesterol levels of Australians and natives of New Guinea from birth to adulthood.Australas Ann Med. 1958; 7: 336-339Google Scholar, 18.De Wolfe M.S. Whyte H.M. Serum cholesterol and lipoproteins in natives of New Guinea and Australians.Australas Ann Med. 1958; 7: 47-54Google Scholar, 20.Casley-Smith J.R. Blood pressures in Australian aborigines.Med J Aust. 1959; 46: 627-633Google Scholar, 21.Maddocks I. Blood pressures in Melanesians.Med J Aust. 1967; 1: 1123-1126Google Scholar, 22.Fleming-Moran M. Santos R.V. Coimbra Junior C.E. Blood pressure levels of the Surui and Zoro Indians of the Brazilian Amazon: group- and sex-specific effects resulting from body composition, health status, and age.Hum Biol. 1991; 63: 835-861Google Scholar, 23.Ghesquiere J.L. Karvonen M.J. Some anthropometric and functional dimensions of the pygmy (Kivu Twa).Ann Hum Biol. 1981; 8: 119-134Google Scholar Neo-normal values can then be regarded as excessive to our paleophysiological and genetic heritage; hence, the benefit in risk reduction seen with therapies that return values closer to our original set points. The general concept that our genetic heritage has been greatly outpaced by our modern environment, thus leading to increased weight, blood pressure, insulin resistance, and other medical problems, is forwarded by the ‘thrifty-genotype’ hypothesis.25.Diamond J.M. Human evolution. Diabetes running wild.Nature. 1992; 357: 362-363Google Scholar ‘Thrifty’ genes, which predispose us to low metabolic rates and salt conservation, evolved to preserve energy and blood pressure in Paleolithic humans faced with shortages in energy, salt, and with high physical demands.26.Sharma A.M. The thrifty-genotype hypothesis and its implications for the study of complex genetic disorders in man.J Mol Med. 1998; 76: 568-571Google Scholar Now faced with an abundance of food and sedentary lifestyles in modern humans, these thrifty genes have become associated with disease. Isolated or ‘primitive’ cultures may arguably be the nearest representation of ‘normal’ human reference populations with respect to our genetic heritage. Many such populations have been identified, whose average blood pressures and cholesterol levels are very low, accompanied by low rates of cardiovascular disease.27.James G. Baker P. Human Population Biology and Blood Pressure: Evolutional and Ecological Considerations and Interpretations of Population Studies. 2nd edn. Raven Press, New York1995Google Scholar Furthermore, blood pressure and serum cholesterol values do not increase with age as is commonly observed outside these isolated cultures. Regardless of the explanation for such phenomena, whether it be low salt consumption28.Page L.B. Epidemiologic evidence on the etiology of human hypertension and its possible prevention.Am Heart J. 1976; 91: 527-534Google Scholar or high intake of cocoa,29.Hollenberg N.K. Martinez G. McCullough M. et al.Aging, acculturation, salt intake, and hypertension in the Kuna of Panama.Hypertension. 1997; 29: 171-176Google Scholar free-living people with average lifetime blood pressures of 90/60 mmHg are not hypotensive, but rather healthy and free from the cardiovascular morbidity and mortality so prevalent elsewhere. Thus, from the vantage point of primitive anthropomorphism, almost every adult in the United States and indeed most of the world has abnormally high blood pressure. The National Cholesterol Education Program does not define a cutoff value for ‘hypercholesterolemia’.30.Executive Summary of The Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III).JAMA. 2001; 285: 2486-2497Google Scholar Rather, the evidence-based guidelines for the prevention of cholesterol-associated disease include individualized treatment goals. For example, the treatment goal for a diabetic is different than the goal serum cholesterol level for someone with no cardiovascular risk factors. Furthermore, results from current and future trials will likely lead to adjusted guidelines and lower targets. Epidemiologic evidence supports a continuous log-linear relationship between total serum cholesterol, low-density lipoprotein (LDL) cholesterol, and the risk of coronary heart disease in the general population.31.Grundy S.M. Cleeman J.I. Merz C.N. et al.Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines.Arterioscler Thromb Vasc Biol. 2004; 24: e149-e161Google Scholar, 32.Law M.R. Wald N.J. Rudnicka A.R. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis.BMJ. 2003; 326: 1423Google Scholar The continuous relationship persists down to an LDL as low as 40 mg/dl, with every 30 mg/dl higher LDL associated with a 30% increase in the relative risk of coronary heart disease.31.Grundy S.M. Cleeman J.I. Merz C.N. et al.Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines.Arterioscler Thromb Vasc Biol. 2004; 24: e149-e161Google Scholar Newer randomized trials similarly support the notion that lower is better. Data from the Heart Protection Study showed that all subgroups of high-risk individuals, including those whose starting pretrial LDL was <100 mg/dl, benefited from LDL-lowering therapy.33.MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebo-controlled trial.Lancet. 2002; 360: 7-22Google Scholar These results were echoed by the PROVE IT study (Pravastatin or Atorvastatin Evaluation and Infection – Thrombolysis in Myocardial Infarction 22) in which a significantly lower risk of death or cardiovascular morbidity was obtained in high-risk patients with an achieved LDL of 62 mg/dl compared to 95 mg/dl.34.Cannon C.P. Braunwald E. McCabe C.H. et al.Intensive versus moderate lipid lowering with statins after acute coronary syndromes.N Engl J Med. 2004; 350: 1495-1504Google Scholar Strikingly similar scenarios exist for blood pressure and albuminuria, as will be discussed. Taking a page from the cholesterol playbook, the appropriate approach to blood pressure and urinary albumin excretion would be abandonment of ‘hypertension’ and ‘microalbuminuria’, and adoption of evidence-based treatment goals. Blood pressure and blood pressure-associated disease should replace ‘hypertension’ in our lexicon. As pointed out by Rose,35.Rose G. Sick individuals and sick populations.Int J Epidemiol. 2001; 30 (discussion 433–424): 427-432Google Scholar and subsequently quoted by MacMahon et al.,36.MacMahon S. Neal B. Rodgers A. Hypertension – time to move on.Lancet. 2005; 365: 1108-1109Google Scholar high blood pressure can be operationally defined as the level at which further reductions do not lead to additional benefits. Treatment targets thus may differ among different comorbid groups, and targets are likely to change with future randomized trials of more intensive blood pressure lowering. In 1978, Anderson reported that re-examination of the Framingham Cohort unsmoothed blood pressure data revealed no additional benefits to DBP<90 mmHg vis-a-vis cardiovascular disease.37.Anderson T.W. Re-examination of some of the Framingham blood-pressure data.Lancet. 1978; 2: 1139-1141Google Scholar A year later, Stewart38.Stewart I.M. Relation of reduction in pressure to first myocardial infarction in patients receiving treatment for severe hypertension.Lancet. 1979; 1: 861-865Google Scholar proposed the concept of the J-curve, and this was followed by confirmation of the J-curve for DBP in participants of several blood pressure-lowering trials.39.Untreated mild hypertension. A Report by the Management Committee of the Australian Therapeutic Trial in Mild Hypertension.Lancet. 1982; 1: 185-191Google Scholar, 40.Cooper S.P. Hardy R.J. Labarthe D.R. et al.The relation between degree of blood pressure reduction and mortality among hypertensives in the Hypertension Detection and Follow-Up Program.Am J Epidemiol. 1988; 127: 387-403Google Scholar, 41.Jafar T.H. Stark P.C. Schmid C.H. et al.Progression of chronic kidney disease: the role of blood pressure control, proteinuria, and angiotensin-converting enzyme inhibition: a patient-level meta-analysis.Ann Intern Med. 2003; 139: 244-252Google Scholar, 42.Berl T. Hunsicker L.G. Lewis J.B. et al.Impact of achieved blood pressure on cardiovascular outcomes in the irbesartan diabetic nephropathy trial.J Am Soc Nephrol. 2005; 16: 2170-2179Google Scholar Arguments against the J-curve hold that the increase in events at the lower end of the spectrum are, in fact, a result of reverse causality, in that coexistent comorbid disease such as congestive heart failure or vascular disease is responsible for both the higher risk of events and lower SBP or DBP. Indeed, a 2004 examination of Framingham data implicates pre-existing cardiovascular disease as an explanation of higher risk at lower DBPs. The authors reported that the risk of cardiovascular events at DBP<90 mmHg was higher only among those with SBP>140 mmHg, suggesting that the J-curve for DBP may be explained by a widened pulse pressure and high SBP; when SBP was <140 mmHg, lower DBP decreased the risk of cardiovascular disease.43.Kannel W.B. Wilson P.W. Nam B.H. et al.A likely explanation for the J-curve of blood pressure cardiovascular risk.Am J Cardiol. 2004; 94: 380-384Google Scholar Moreover, many other trials have failed to show a J-curve,44.SHEP Cooperative Research Group Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP).JAMA. 1991; 265: 3255-3264Google Scholar, 45.Schrier R.W. Estacio R.O. Esler A. Mehler P. Effects of aggressive blood pressure control in normotensive type 2 diabetic patients on albuminuria, retinopathy and strokes.Kidney Int. 2002; 61: 1086-1097Google Scholar, 46.Nissen S.E. Tuzcu E.M. Libby P. et al.Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial.JAMA. 2004; 292: 2217-2225Google Scholar whereas others demonstrating a J-curve could not fully account for baseline comorbidity such as the severity of pre-existing heart failure and vascular disease.41.Jafar T.H. Stark P.C. Schmid C.H. et al.Progression of chronic kidney disease: the role of blood pressure control, proteinuria, and angiotensin-converting enzyme inhibition: a patient-level meta-analysis.Ann Intern Med. 2003; 139: 244-252Google Scholar, 42.Berl T. Hunsicker L.G. Lewis J.B. et al.Impact of achieved blood pressure on cardiovascular outcomes in the irbesartan diabetic nephropathy trial.J Am Soc Nephrol. 2005; 16: 2170-2179Google Scholar Finally, in an analysis that combined individual data from almost one million participants with no baseline cardiovascular disease from 61 prospective studies, there was a linear association between both SBP and DBP and risk of cardiovascular mortality down to 115 mmHg SBP and 75 mmHg DBP. At blood pressures below these values, the risk of cardiovascular mortality was even lower.47.Lewington S. Clarke R. Qizilbash N. et al.Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies.Lancet. 2002; 360: 1903-1913Google Scholar The linear relationship between blood pressure and cardiovascular death just mentioned is reminiscent of the association between cholesterol and risk of coronary heart disease. Down to a blood pressure of 115/75 mmHg, every 10 mmHg lower usual systolic or 5 mmHg lower usual diastolic pressure is associated during long-term follow-up with a 40% reduction in risk of death from stroke and a 30% reduction in risk of death from ischemic heart disease.47.Lewington S. Clarke R. Qizilbash N. et al.Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies.Lancet. 2002; 360: 1903-1913Google Scholar These findings are consistent with other observational studies,48.MacMahon S. Peto R. Cutler J. et al.Blood pressure, stroke, and coronary heart disease. Part 1. Prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias.Lancet. 1990; 335: 765-774Google Scholar and once again argues that our current definition of normal be re-evaluated. Results from randomized controlled trials have confirmed that a further reduction in blood pressure among ‘normotensive’ individuals indeed lowers the risk of cardiovascular events (Table 1 ). These studies include populations where the absolute risk of cardiovascular outcomes is high, such as diabetes,45.Schrier R.W. Estacio R.O. Esler A. Mehler P. Effects of aggressive blood pressure control in normotensive type 2 diabetic patients on albuminuria, retinopathy and strokes.Kidney Int. 2002; 61: 1086-1097Google Scholar, 49.Yusuf S. Sleight P. Pogue J. et al.Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators.N Engl J Med. 2000; 342: 145-153Google Scholar, 50.Mehler P.S. Coll J.R. Estacio R. et al.Intensive blood pressure control reduces the risk of cardiovascular events in patients with peripheral arterial disease and type 2 diabetes.Circulation. 2003; 107: 753-756Google Scholar coronary artery disease,46.Nissen S.E. Tuzcu E.M. Libby P. et al.Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial.JAMA. 2004; 292: 2217-2225Google Scholar, 49.Yusuf S. Sleight P. Pogue J. et al.Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators.N Engl J Med. 2000; 342: 145-153Google Scholar, 51.Fox K.M. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study).Lancet. 2003; 362: 782-788Google Scholar and cerebrovascular disease,52.Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack.Lancet. 2001; 358: 1033-1041Google Scholar a requirement necessary to achieve adequate statistical power during the relatively short duration of a randomized trial.Table 1Randomized trials of blood pressure reduction involving high-risk ‘normotensive’ individualsStudyPopulation (normotensive subset)Entry BP (mmHg) (normotensive subset)InterventionBP reduction (mm/Hg)OutcomeRisk reduction (normotensive subset) (%)HOPEKnown vascular disease or diabetes plus one other CV risk factorn=4942Not given(presumed <140/90)Ramipril3/2 (study visits)10/4 (24 ABPM)Composite of CV death, nonfatal stroke, nonfatal MI20PROGRESSaThe PROGRESS and EUROPA trials defined hypertension as BP≥160/90 mmHg; the CAMELOT defined hypertension as DBP≥100 mmHg. However, mean BP in PROGRESS and CAMELOT were 136/79 mmHg and 129/78 mmHg, respectively. In EUROPA, the BP for the entire cohort (both hypertensive and normotensive) was 137/82 mmHg – presumably the normotensive group had a lower mean entry BP.Prior stroke or TIAn=3189136/79Perindopril orPerindopril plus indapamide5/3 (single drug)12/5 (combination)Recurrent strokeComposite of CV death, nonfatal stroke, nonfatal MI2724EUROPAaThe PROGRESS and EUROPA trials defined hypertension as BP≥160/90 mmHg; the CAMELOT defined hypertension as DBP≥100 mmHg. However, mean BP in PROGRESS and CAMELOT were 136/79 mmHg and 129/78 mmHg, respectively. In EUROPA, the BP for the entire cohort (both hypertensive and normotensive) was 137/82 mmHg – presumably the normotensive group had a lower mean entry BP.Known CADn=8906Not given(mean for entire cohort 137/82)Perindopril5/2Composite of CV death, nonfatal MI, cardiac arrest20CAMELOTaThe PROGRESS and EUROPA trials defined hypertension as BP≥160/90 mmHg; the CAMELOT defined hypertension as DBP≥100 mmHg. However, mean BP in PROGRESS and CAMELOT were 136/79 mmHg and 129/78 mmHg, respectively. In EUROPA, the BP for the entire cohort (both hypertensive and normotensive) was 137/82 mmHg – presumably the normotensive group had a lower mean entry BP.Angiographically confirmed CADn=1991129/78Amlodipine orEnalapril5/2.5Composite of CV death, MI, stroke, TIA, PVD, CHF, ACS, cardiac arrest31 (amlodipine)19 (enalapril, NS)ABCDType II DMn=480136/84Nisoldipine orEnalapril9/6Stroke70ABCD=Appropriate Blood pressure Control in Diabetes; ABPM=24 h ambulatory blood pressure monitoring; ACS=acute coronary syndrome; CAD=coronary artery disease; CAMELOT=Comparison of Amlodipine; CHF=congestive heart failure; CV=cardiovascular; DM=diabetes; EUROPA=EURopean trial On reduction of cardiac events with Perindopril with stable coronary Artery disease; HOPE=Heart Outcomes Prevention Evaluation; MI=myocardial infarction; NS=nonsignificant; PVD=peripheral vascular disease; PROGRESS=Perindopril pROtection aGainst REcurrent Stroke Study; TIA=transient ischemic attack.a The PROGRESS and EUROPA trials defined hypertension as BP≥160/90 mmHg; the CAMELOT defined hypertension as DBP≥100 mmHg. However, mean BP in PROGRESS and CAMELOT were 136/79 mmHg and 129/78 mmHg, respectively. In EUROPA, the BP for the entire cohort (both hypertensive and normotensive) was 137/82 mmHg – presumably the normotensive group had a lower mean entry BP. Open table in a new tab ABCD=Appropriate Blood pressure Control in Diabetes; ABPM=24 h ambulatory blood pressure monitoring; ACS=acute coronary syndrome; CAD=coronary artery disease; CAMELOT=Comparison of Amlodipine; CHF=congestive heart failure; CV=cardiovascular; DM=diabetes; EUROPA=EURopean trial On reduction of cardiac events with Perindopril with stable coronary Artery disease; HOP" @default.
• W1984037141 created "2016-06-24" @default.
• W1984037141 creator A5016263167 @default.
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• W1984037141 date "2006-01-01" @default.
• W1984037141 modified "2023-09-24" @default.
• W1984037141 title "‘Hypertension’ and ‘microalbuminuria’: The bell tolls for thee" @default.
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• W1984037141 doi "https://doi.org/10.1038/sj.ki.5000056" @default.
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