Semin Vasc Med 2002; 02(4): 355-368
DOI: 10.1055/s-2002-36765
Copyright © 2002 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Blood Pressure and Coronary Heart Disease: A Review of the Evidence

Carlene M.M. Lawes1 , Derrick A. Bennett1 , Sarah Lewington2 , Anthony Rodgers1
  • 1Clinical Trials Research Unit, Department of Medicine, University of Auckland, New Zealand
  • 2Clinical Trial Service Unit and Epidemiology Studies Unit, Radcliffe Infirmary, University of Oxford, United Kingdom
Further Information

Publication History

Publication Date:
22 January 2003 (online)

ABSTRACT

Overviews of randomized controlled trials and prospective observational studies provide the most reliable data on the association between blood pressure and coronary heart disease (CHD). The totality of evidence indicates a strong association between blood pressure and CHD, which is continuous down to levels of at least 115 mm Hg systolic. Overall, for those 60 to 69 years of age, a 10 mm Hg lower systolic blood pressure is associated with about one-fifth lower risk of a CHD event. The size and shape of this association is consistent across regions, for males and females, and for fatal events as well as nonfatal myocardial infarction.

Trials comparing active treatment to placebo or no treatment have demonstrated that the benefits of blood pressure lowering with different classes of drugs (e.g., diuretics, beta-blockers, ACE inhibitors, calcium antagonists) are broadly similar, with approximately one-fifth reduction in CHD. ACE inhibitors achieve this with relatively modest blood pressure reductions, but the size of the reduction for calcium antagonists remains uncertain and appears somewhat less than expected from the blood pressure reduction. Trials confirm the expectation from cohort studies of benefits increasing with the amount of blood pressure lowering, and benefit accruing among those with average or even below average blood pressure. Observational data suggest that the proportional association is attenuated with age, but attenuation is less evident in trial data. However, in both cohort studies and clinical trials, CHD risk differences associated with a given blood pressure difference increase with age.

The important points to emerge from this review are, first, that the relative benefits of blood pressure lowering for CHD prevention are likely to be consistent across a range of different populations. Second, there is likely to be considerable benefit with blood pressure lowering below "traditional" hypertension thresholds, especially in those with high absolute risk. Third, initiating and maintaining the maximum tolerated blood pressure reduction is a more important issue than choice of initial agent. Finally, and most importantly, the large majority of people have suboptimal blood pressure (e.g., systolic > 115 mm Hg) and so initiatives to lower blood pressure population-wide are an essential adjunct to targeted treatment programs.

REFERENCES

  • 1 Swales J. Textbook of Hypertension.  Oxford: Blackwell Scientific; 1994
  • 2 Warlow C, Dennis M, VanGijn J. Stroke: A Practical Guide to Management.  1st ed. Oxford: Blackwell Science 1996
  • 3 Bronner L L, Kanter D S, Manson J E. Primary prevention of stroke.  N Engl J Med . 1995;  333 1392-1400
  • 4 Leppala J M, Virtamo J, Fogelholm R, Albanes D, Heinonen O P. Different risk factors for different stroke subtypes: association of blood pressure, cholesterol, and antioxidants.  Stroke . 1999;  30 2535-2540
  • 5 MacMahon S, Peto R, Cutler J. Blood pressure, stroke, and coronary heart disease. Part I, Prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias.  Lancet . 1990;  335 765-774
  • 6 Clarke R, Shipley M, Lewington S. Underestimation of risk associations due to regression dilution in long-term follow-up of prospective studies.  Am J Epidemiol . 1999;  150 341-353
  • 7 Kannel W B, Wolf P A, Verter J, McNamara P M. Epidemiologic assessment of the role of blood pressure in stroke. The Framingham Study.  JAMA . 1970;  214 301-310
  • 8 Kannel W B, Gordon T, Schwartz M J. Systolic versus diastolic blood pressure and risk of coronary heart disease. The Framingham Study.  Am J Cardiol . 1971;  27 335-346
  • 9 Stamler J, Neaton J D, Wentworth D N. Blood pressure (systolic and diastolic) and risk of fatal coronary heart disease.  Hypertension . 1989;  13(Suppl) I2-I12
  • 10 Stamler J, Stamler R, Neaton J D. Blood pressure, systolic and diastolic, and cardiovascular risks. US population data.  Arch Intern Med . 1993;  153 598-615
  • 11 Mitchell G F, Moye L A, Braunwald E. Sphygmomanometrically determined pulse pressure is a powerful independent predictor of recurrent events after myocardial infarction in patients with impaired left ventricular function. Survival and Ventricular Enlargement Investigators.  Circulation . 1997;  96 4254-4260
  • 12 Franklin S S. Aging and hypertension: the assessment of blood pressure indices in predicting coronary heart disease.  J Hypertens . 1999;  17(Suppl) S29-S36
  • 13 Miura K, Dyer A R, Greenland P. Pulse pressure compared with other blood pressure indexes in the prediction of 25-year cardiovascular and all-cause mortality rates: the Chicago Heart Association Detection Project in Industry Study.  Hypertension . 2001;  38 232-237
  • 14 Franklin S S, Larson M G, Khan S A. Does the relation of blood pressure to coronary heart disease risk change with aging?.  <~>The Framingham Heart Study. Circulation . 2001;  103 1245-1249
  • 15 Benetos A, Safar M, Rudnichi A. Pulse pressure: a predictor of long-term cardiovascular mortality in a French male population.  Hypertension . 1997;  30 1410-1415
  • 16 Benetos A, Rudnichi A, Safar M, Guize L. Pulse pressure and cardiovascular mortality in normotensive and hypertensive subjects.  Hypertension . 1998;  32 560-564
  • 17 Benetos A. Pulse pressure and cardiovascular risk.  J Hypertens . 1999;  17(Suppl 5) S21-S24
  • 18 Prospective Studies Collaboration. Cholesterol, diastolic blood pressure, and stroke: 13,000 strokes in 45,000 people in 45 prospective cohorts.  Lancet . 1995;  346 1647-1653
  • 19 Eastern Stroke and Coronary Heart Disease Collaborative Research Group. Blood pressure, cholesterol, and stroke in eastern Asia.  Lancet . 1998;  352 1801-1807
  • 20 Asia-Pacific Cohort Studies Collaboration. Determinants of cardiovascular disease in the Asia-Pacific region: protocol for a collaborative overview of cohort studies.  Cardiovasc Prev . 1999;  2 281-289
  • 21 Prospective Studies Collaboration. Collaborative overview ("meta-analysis") of prospective observational studies of the associations of usual blood pressure and usual cholesterol levels with common causes of death: protocol for the second cycle of the Prospective Studies Collaboration.  J Cardiovasc Risk . 1999;  6 315-320
  • 22 Asia Pacific Cohort Studies Collaboration. Cardiovascular disease in the Asia Pacific region (in press).  J Hypertens. 2002; 
  • 23 Collins R, Peto R, MacMahon S. Blood pressure, stroke, and coronary heart disease. Part 2, Short-term reductions in blood pressure: overview of randomised drug trials in their epidemiological context.  Lancet . 1990;  335 827-838
  • 24 MacMahon S, Rodgers A. The effects of anti-hypertensive treatment on vascular disease: reappraisal of the evidence in 1994.  J Vasc Med Biol . 1993;  4 265-271
  • 25 MacMahon S, Rodgers A. The effects of blood pressure reduction in older patients: an overview of five randomized controlled trials in elderly hypertensives.  Clin Exp Hypertens (New York) . 1993;  15 967-978
  • 26 Insua J T, Sacks H S, Lau T S. Drug treatment of hypertension in the elderly: a meta-analysis.  Ann Intern Med . 1994;  121 355-362
  • 27 Gueyffier F, Boutitie F, Boissel J P. Effect of antihypertensive drug treatment on cardiovascular outcomes in women and men. A meta-analysis of individual patient data from randomized, controlled trials. The INDANA Investigators.  Ann Intern Med . 1997;  126 761-767
  • 28 He J, Whelton P K. Elevated systolic blood pressure as a risk factor for cardiovascular and renal disease.  J Hypertens . 1999;  17(Suppl) S7-S13
  • 29 Gueyffier F, Boutitie F, Boissel J P. INDANA: a meta-analysis on individual patient data in hypertension. Protocol and preliminary results.  Therapie . 1995;  50 353-362
  • 30 Gueyffier F, Froment A, Gouton M. New meta-analysis of treatment trials of hypertension: improving the estimate of therapeutic benefit.  J Hum Hypertens . 1996;  10 1-8
  • 31 Progress Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack.  Lancet . 2001;  358 1033-1041
  • 32 Neal B, MacMahon S, Chapman N. Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: results of prospectively designed overviews of randomised trials. Blood Pressure Lowering Treatment Trialists' Collaboration.  Lancet . 2000;  356 1955-1964
  • 33 Hedges L V, Olkin I. Statistical Methods for Meta-Analysis.  San Diego, CA: Academic Press 1985
  • 34 DerSimonian R, Laird N. Meta-analysis in clinical trials.  Control Clin Trials . 1986;  7 177-88
  • 35 Light R J, Pillemer D B. Summing Up. The Science of Reviewing Research Cambridge, MA: Harvard University Press 1984
  • 36 Jousilahti P, Vartiainen E, Tuomilehto J, Puska P. Sex, age, cardiovascular risk factors, and coronary heart disease: a prospective follow-up study of 14,786 middle-aged men and women in Finland.  Circulation . 1999;  99 1165-1172
  • 37 Cooper R S, Ford E. Comparability of risk factors for coronary heart disease among blacks and whites in the NHANES-I Epidemiologic Follow-up Study.  Ann Epidemiol . 1992;  2 637-645
  • 38 Keil J E, Sutherland S E, Knapp R G. Mortality rates and risk factors for coronary disease in black as compared with white men and women.  New Engl J Med . 1993;  329 73-78
  • 39 Haheim L L, Holme I, Hjermann I, Leren P. The predictability of risk factors with respect to incidence and mortality of myocardial infarction and total mortality. A 12-year follow-up of the Oslo Study, Norway.  J Intern Med . 1993;  234 17-24
  • 40 Keil J E, Sutherland S E, Hames C G. Coronary disease mortality and risk factors in black and white men. Results from the combined Charleston, SC, and Evans County, Georgia, heart studies.  Arch Intern Med . 1995;  155 1521-1527
  • 41 Garcia-Palmieri Jr M R. Risk factors of coronary heart disease: a prospective epidemiologic study in Puerto Rico. In: Yu PH GJ, ed. Progress in Cardiology Philadelphia: Lea and Febiger 1986: 101-190
  • 42 Psaty B M, Furberg C D, Kuller L H. Association between blood pressure level and the risk of myocardial infarction, stroke, and total mortality: the cardiovascular health study.  Arch Intern Med . 2001;  161 1183-192
  • 43 Neaton J D, Wentworth D. Serum cholesterol, blood pressure, cigarette smoking, and death from coronary heart disease. Overall findings and differences by age for 316,099 white men. Multiple Risk Factor Intervention Trial Research Group.  Arch Intern Med . 1992;  152 56-64
  • 44 Hansson L, Zanchetti A, Carruthers S G. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group.  Lancet . 1998;  351 1755-1762
  • 45 Estacio R O, Jeffers B W, Hiatt W R. The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension.  New Engl J Med . 1998;  338 645-652
  • 46 Anonymous. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group.  BMJ . 1998;  317 703-713
  • 47 Anonymous. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. UK Prospective Diabetes Study Group.  BMJ . 1998;  317 713-720
  • 48 Hansson L, Lindholm L H, Niskanen L. Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial.  Lancet . 1999;  353 611-616
  • 49 Hansson L, Lindholm L H, Ekbom T. Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity the Swedish Trial in Old Patients with Hypertension-2 study.  Lancet . 1999;  354 1751-1756
  • 50 Casiglia E, Spolaore P, Mazza A. Effect of two different therapeutic approaches on total and cardiovascular mortality in a Cardiovascular Study in the Elderly (CASTEL).  Jpn Heart J . 1994;  35 589-600
  • 51 Borhani N O, Mercuri M, Borhani P A. Final outcome results of the Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS). A randomized controlled trial.  JAMA . 1996;  276 785-791
  • 52 Zanchetti A, Rosei E A, Dal Palu C. The Verapamil in Hypertension and Atherosclerosis Study (VHAS): results of long-term randomized treatment with either verapamil or chlorthalidone on carotid intima-media thickness.  J Hypertens . 1998;  16 1667-1676
  • 53 Rosei E A, Dal Palu C, Leonetti G. Clinical results of the Verapamil in Hypertension and Atherosclerosis Study. VHAS Investigators.  J Hypertens . 1997;  15 1337-1344
  • 54 Anonymous. Randomized double-blind comparison of a calcium antagonist and a diuretic in elderly hypertensives. National Intervention Cooperative Study in Elderly Hypertensives Study Group.  Hypertension . 1999;  34 1129-1133
  • 55 Hansson L, Hedner T, Lund-Johansen P. Randomised trial of effects of calcium antagonists compared with diuretics and beta-blockers on cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazem (NORDIL) study.  Lancet . 2000;  356 359-365
  • 56 Brown M J, Palmer C R, Castaigne A. Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT).  Lancet . 2000;  356 366-372
  • 57 Tatti P, Pahor M, Byington R P. Outcome results of the Fosinopril Versus Amlodipine Cardiovascular Events Randomized Trial (FACET) in patients with hypertension and NIDDM.  Diabetes Care . 1998;  21 597-603
  • 58 Thompson S G. Why sources of heterogeneity in meta-analysis should be investigated.  BMJ . 1994;  309 1351-1355
  • 59 Gueyffier F, Boissel J P, Boutitie F. Effect of antihypertensive treatment in patients having already suffered from stroke. Gathering the evidence. The INDANA (INdividual Data ANalysis of Antihypertensive intervention trials) Project Collaborators.  Stroke . 1997;  28 2557-2562
  • 60 Anonymous. Major cardiovascular events in hypertensive patients randomized to doxazosin versus chlorthalidone: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). ALLHAT Collaborative Research Group.  JAMA . 2000;  283 1967-1975
  • 61 Dahlof B, Devereux R B, Kjeldsen S E. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol.  Lancet . 2002;  359 995-1003
  • 62 Lindholm L H, Ibsen H, Dahlof B. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol.  Lancet . 2002;  359 1004-1010
  • 63 Stewart I M. Relation of reduction in pressure to first myocardial infarction in patients receiving treatment for severe hypertension.  Lancet . 1979;  1 861-865
  • 64 Kannel W B, D'Agostino R B, Silbershatz H. Blood pressure and cardiovascular morbidity and mortality rates in the elderly.  Am Heart J . 1997;  134 758-763
  • 65 Cruickshank J M. J curve in antihypertensive therapy-does it exist?.  <~>A personal point of view. Cardiovasc Drugs Ther . 1994;  8 757-760
  • 66 D'Agostino R B, Belanger A J, Kannel W B, Cruickshank J M. Relation of low diastolic blood pressure to coronary heart disease death in presence of myocardial infarction: the Framingham Study.  Br Med J . 1991;  303 385-389
  • 67 Farnett L, Mulrow C D, Linn W D, Lucey C R, Tuley M R. The J-curve phenomenon and the treatment of hypertension. Is there a point beyond which pressure reduction is dangerous?.  JAMA . 1991;  265 489-495
  • 68 Alderman M H. Blood pressure J-curve: is it cause or effect?.  Curr Opin Nephrol Hypertens . 1996;  5 209-213
  • 69 MacMahon S, Rodgers A, Neal B, Chalmers J. Blood pressure lowering for the secondary prevention of myocardial infarction and stroke.  Hypertension . 1997;  29 537-538
  • 70 Sleight P. Lowering of blood pressure and artery stiffness.  Lancet . 1997;  349 362
  • 71 Sleight P. Lowering of blood pressure and artery stiffness.  Lancet . 1997;  349 955-956
  • 72 Flack J M, Neaton J, Grimm Jr R. Blood pressure and mortality among men with prior myocardial infarction. Multiple Risk Factor Intervention Trial Research Group.  Circulation . 1995;  92 2437-2445
  • 73 McMurray J, McInnes G T. The J-curve hypothesis.  Lancet . 1992;  339 561-562
  • 74 Pfeffer M A. Angiotensin-converting enzyme inhibition in congestive heart failure: benefit and perspective.  Am Heart J . 1993;  126 789-793
  • 75 Staessen J, Fagard R, Thijs L. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension.  Lancet . 1997;  350 757-764
  • 76 Progress Collaborative Group. The lowering of blood pressure after stroke.  Lancet . 2001;  358 1994-1995
  • 77 Bosch J, Yusuf S, Pogue J. Use of ramipril in preventing stroke: double blind randomised trial.  Br Med J . 2002;  324 699-702
  • 78 Murray C JL, Lopez A D. The Global Burden of Disease. A Comprehensive Assessment of Mortality and Disability from Diseases, Injuries, and Risk Factors in 1990 and Projected to 2020 Cambridge, MA: Harvard University Press 1996
  • 79 Anonymous. The sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure.  Arch Intern Med . 1997;  157 2413-2446
  • 80 Anonymous. 1999 World Health Organization-International Society of Hypertension Guidelines for the Management of Hypertension.  Guidelines Subcommittee. J Hypertens . 1999;  17 151-183
  • 81 Anonymous. The Australian therapeutic trial in mild hypertension. Report by the Management Committee.  Lancet . 1980;  1 1261-1267
  • 82 Anonymous. Control of moderately raised blood pressure. Report of a co-operative randomized controlled trial.  Br Med J . 1973;  3 434-436
  • 83 Carter A B. Hypotensive therapy in stroke survivors.  Lancet . 1970;  1 485-489
  • 84 Coope J, Warrender T S. Randomised trial of treatment of hypertension in elderly patients in primary care.  Br Med J Clin Res Ed . 1986;  293 1145-1151
  • 85 Amery A, Birkenhager W, Brixko P. Mortality and morbidity results from the European Working Party on High Blood Pressure in the Elderly trial.  Lancet . 1985;  1 1349-1354
  • 86 Anonymous. Five-year findings of the hypertension detection and follow-up program. I. Reduction in mortality of persons with high blood pressure, including mild hypertension. Hypertension Detection and Follow-up Program Cooperative Group.  JAMA . 1979;  242 2562-2571
  • 87 Anonymous. Five-year findings of the hypertension detection and follow-up program. II. Mortality by race-sex and age. Hypertension Detection and Follow-up Program Cooperative Group.  JAMA . 1979;  242 2572-2577
  • 88 Anonymous. Five-year findings of the hypertension detection and follow-up program. III. Reduction in stroke incidence among persons with high blood pressure. Hypertension Detection and Follow-up Program Cooperative Group.  JAMA . 1982;  247 633-638
  • 89 Anonymous. The effect of treatment on mortality in "mild" hypertension: results of the hypertension detection and follow-up program.  New Engl J Med . 1982;  307 976-980
  • 90 Anonymous. Effect of stepped care treatment on the incidence of myocardial infarction and angina pectoris. 5-Year findings of the hypertension detection and follow-up program.  Hypertension . 1984;  6 I198-206
  • 91 Anonymous. Effect of antihypertensive treatment on stroke recurrence. Hypertension-Stroke Cooperative Study Group.  JAMA . 1974;  229 409-418
  • 92 Anonymous. Medical Research Council trial of treatment of hypertension in older adults: principal results. MRC Working Party.  Br Med J . 1992;  304 405-412
  • 93 Anonymous. MRC trial of treatment of mild hypertension: principal results. Medical Research Council Working Party.  Br Med J Clin Res Ed . 1985;  291 97-104
  • 94 Helgeland A. Treatment of mild hypertension: a five year controlled drug trial. The Oslo study.  Am J Med . 1980;  69 725-732
  • 95 Leren P, Helgeland A. Oslo Hypertension study.  Drugs . 1986;  31(Suppl 1) 41-45
  • 96 Anonymous. 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). SHEP Cooperative Research Group.  JAMA . 1991;  265 3255-3264
  • 97 Dahlof B, Lindholm L H, Hansson L. Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension).  Lancet . 1991;  338 1281-1285
  • 98 Smith W M. Treatment of mild hypertension: results of a ten-year intervention trial.  Circ Res . 1977;  40(Suppl 1) I98-105
  • 99 Anonymous. Effects of treatment on morbidity in hypertension. Results in patients with diastolic blood pressures averaging 115 through 129 mm Hg.  JAMA . 1967;  202 1028-1034
  • 100 Anonymous. Effects of treatment on morbidity in hypertension. II. Results in patients with diastolic blood pressure averaging 90 through 114 mm Hg.  JAMA . 1970;  213 1143-1152
  • 101 Perry Jr M H. Treatment of mild hypertension. Preliminary results of a two-year feasibility trial.  Circ Res . 1977;  40(Suppl 1) I180-187
  • 102 Anonymous. Evaluation of drug treatment in mild hypertension: VA-NHLBI feasibility trial. Plan and preliminary results of a two-year feasibility trial for a multicenter intervention study to evaluate the benefits versus the disadvantages of treating mild hypertension. Prepared for the Veterans Administration-National Heart, Lung, and Blood Institute Study Group for Evaluating Treatment in Mild Hypertension.  Ann NY Acad Sci . 1978;  304 267-292
  • 103 Wolff F W, Lindeman R D. Effects of treatment in hypertension. Results of a controlled study.  J Chron Dis . 1966;  19 227-240
  • 104 Yusuf S, Sleight P, Pogue J. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators.  New Engl J Med . 2000;  342 145-153
  • 105 MacMahon S, Sharpe N, Gamble G. Randomized, placebo-controlled trial of the angiotensin-converting enzyme inhibitor, ramipril, in patients with coronary or other occlusive arterial disease. PART-2 Collaborative Research Group. Prevention of Atherosclerosis with Ramipril.  J Am Coll Cardiol . 2000;  36 438-443
  • 106 Cashin-Hemphill L, Holmvang G, Chan R C. Angiotensin-converting enzyme inhibition as antiatherosclerotic therapy: no answer yet. QUIET Investigators. QUinapril Ischemic Event Trial.  Am J Cardiol . 1999;  83 43-47
  • 107 Teo K K, Burton J R, Buller C E. Long-term effects of cholesterol lowering and angiotensin-converting enzyme inhibition on coronary atherosclerosis: the Simvastatin/Enalapril coronary atherosclerosis trial (SCAT).  Circulation . 2000;  102 1748-1754
  • 108 Pitt B, Byington R P, Furberg C D. Effect of amlodipine on the progression of atherosclerosis and the occurrence of clinical events.  Circulation . 2000;  102 1503-1510
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