No 49: Hypertension, Blood Pressure and living longer - Everything you ever wanted to know
tldr
The below article summarises the history of: measuring blood pressure (BP); establishing that hypertension is dangerous; the treatments for lowering BP and the current management. Its a deep dive with a list of “the key papers in the field” at the end.
Reading about this topic and summarising it was far more interesting that I originally thought it would be. If you are studying to be a GP or physician then I think this article will tell you all you really need to know.
If you are interested in the history of medicine or medications, then you might be interested to see the previously articles on this topic:
What I'd like to know about the history of medications
A history of diabetes mangement
This week’s Deep Dive is on blood pressure (BP), hypertension (HTN), medications, guidelines and preventing death!
Death = heart attacks (MIs), heart failure, strokes (TIA/CVD) and kidney disease (CKD)
The absolute basic facts:
Hypertension (HTN) can be divided into Primary or Essential Hypertension and Secondary Hypertension.
“Healthy” individuals can have a remarkably high blood pressure (BP)
BP tends to increase with age
Long term high BP “damages” the arteries.
Reduced arterial function leads to reduce blood flow to the organs and this has a detrimental effect on the brain, heart, kidneys and other organs.
This article is excellent and was the basis for my further reading - Saklayen MG, Deshpande NV. Timeline of History of Hypertension Treatment. Front Cardiovasc Med. 2016 Feb 23;3:3. doi: 10.3389/fcvm.2016.00003. PMID: 26942184; PMCID: PMC4763852.
When was the condition described and by who?
2600 BC - The Egyptians knew how to assess the pulse and noticed a “hard pulse”
2600 BC – 201 AD – Venesection was the recommended treatment by Egyptian, Chinese, middle eastern, Greek and Roman doctors including Hippocrates and Galen.
1733 - Stephen Hales (1677 – 1761) first described the concept of “blood pressure”
1828 – Poiseuille invents the mercury manometer for measuring arterial BP
1847 – Carl Ludwig invented the kymograph which allowed for the graphical method of recording clinical data
1854 – Vierordt invents the sphygmomanometer for non-invasive BP measurement
1856 – Faivre establishes “normal arterial pressure” as 120 mmHg
Frederick Akbar Mahomed (1849–1884), an Irish-Indian physician working at Guy’s hospital in London, first described conditions that later came to be known as “essential hypertension”
1896 – Riva-Rocci describes the modern method of brachial BP measurement
1905 – Korotkoff describes how he uses a stethoscope to determine the systolic and diastolic BP – his paper is only 207 words long!
1924 – “hypertonie essential” was used by Frank
1945 - President Franklin D. Roosevelt had a BP of 220/120 and then died of a stroke. This was a pivotal moment in the realisation that hypertension could kill and sparked a wave of research investment to find a cure.
1961 – the concept that multiple factors are required to increase the risk of CHD is proposed by the Framingham Study investigators
In the early 20th century there were a number of myths about HTN such as,
It was “benign”
It was normal for BP to increase with age
The heart compensate well for HTN and this was “normal”
An isolated raised systolic did not require reduction and it would in fact be dangerous to lower.
Originally, diastolic BP was thought to be more dangerous than systolic BP
Women were thought to tolerate HTN better than men without increased risk
Safe and “normal” BP measurements were originally your age + 100, so age 70 = SBP of 170/90. However, this was again shown to increase your mortality.
We now know that even a “normal BP” of <120/80 does not fully reduce your risk of CHD or stroke.
What are the signs and symptoms?
Mostly none until there is end organ damage or headache and blurred vision.
What is the prevalence?
1970 – a BP of 160/90 was defined as systolic HTN and prevalence in a retirement community was estimated at 3%.
>160/90 was associated with increased cardiac mortality.
1971 – HTN was 12% in white men and 37% in black men in an American sample. The prevalence in women appeared to be higher.
4. What is the natural course?
HTN increases your risk of: CHD/MI, stroke, heart failure, CKD, PVD.
HTN + obesity + high blood sugar + high blood lipids + smoking = most risk = metabolic syndrome
1/6 – the lifetime risk of a stroke.
What is the natural mortality and morbidity rate?
“many patients live medically uneventful lives in spite of prolonged and considerable blood pressure elevation.”
HTN = 4x the stroke risk of someone with BP <120/80
An increase of 20/10 in your BP = 2x your risk of stroke and CHD deaths
CHD Mortality was strongly associated with: cholesterol >4.65 mmol/L (180 mg/dL); systolic BP >110 mm Hg; and diastolic BP >70 mm Hg
normotensive at 55 years of age = 90% lifetime risk of developing HTN
Are you likely to die from this or something else?
Difficult to say
What was the first treatment and was it effective?
1900 – Sodium thiocyanate was used for HTN by Treupel and Edinger
1904 – Sodium restriction was recommended
1923 – The first sympathectomy operation by Fritz Bruening and Kraus
1959 - Hydralazine
1950 – Pentaquine, bretylium, guanethidine
1953 – chemical sympathectomy = tetraethylammonium chloride, hexamethonium
1957 – the first effective oral diuretic – chlorothiazide by Freis, Wilson and Parish
1960 - Alpha-methyl-dopa by Oates, Gillepsie and Udenfriend
1964 – Propranolol (Beta-Blocker) by Prichard and Gillam
1980 – ACEi – Captopril and Enalapril by John Alexander of Squibb and John Laragh. It had the benefit of not causing lethargy like B-blockers but did cause hyperkalaemia.
1985 - MRC trial of treatment of mild hypertension: principal results. Medical Research Council Working Party. Br Med J (Clin Res Ed). 1985 Jul 13;291(6488):97-104. doi: 10.1136/bmj.291.6488.97. PMID: 2861880; PMCID: PMC1416260. = Primary prevention was not statistically improved but bendrofluazide seemed to reduce all cause mortality more than propranolol did.
1995 – Losartan was the first ARB to be approved by the FDA. The AT1 receptors mediate vasoconstriction, aldosterone release, renal sodium reabsorption and vasopressin secretion. ARBs are blocking the last part of the renin–angiotensin pathway and block the pathway more specifically than ACE inhibitors
When was the first trial? And by whom?
1967 - Effects of treatment on morbidity in hypertension. Results in patients with diastolic blood pressures averaging 115 through 129 mm Hg. JAMA. 1967 Dec 11;202(11):1028-34. PMID: 4862069. – The first RCT for BP control.
What is the current management?
· https://www.nice.org.uk/guidance/ng136
· https://www.nice.org.uk/guidance/NG136/resources
· HTN = ABCD
· ACEi or ARB first, especially if diabetic
· CCB first if black, >55 years old and not diabetic.
· Step 2 = A+C or A+D or C+D
· 2nd line = thiazide-like diuretic, such as indapamide in preference to a conventional thiazide diuretic such as bendroflumethiazide or hydrochlorothiazide.
· Step 3 = ACD
· Step 4 = ACD + low-dose spironolactone potassium < 4.5 mmol/l.
· ACD + alpha-blocker or beta-blocker if potassium > 4.5 mmol/l.
· US Guidance
1. First line = Thiazide diuretic = anyone with uncomplicated HTN >140/90
2. For anyone with 20/10 > target should have an additional agent
3. ACEi, ARB, B-blocker, CCB
4. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ; Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. National Heart, Lung, and Blood Institute; National High Blood Pressure Education Program Coordinating Committee. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003 Dec;42(6):1206-52. doi: 10.1161/01.HYP.0000107251.49515.c2. Epub 2003 Dec 1. PMID: 14656957.
What is the risk reduction?
Monotherapy = approx. 30% relative risk reduction in mortality after 5 years.
What is the NNT for each medication?
ACEi NNT for all cause mortality = 70
ACEi NNT for cardiovascular mortality = 124
ACEi NNT for cerebrovascular mortality = 1415
ARB NNT for all cause morality = 446
J.J. Mourad, J. Brugts, M. Bertrand, Number needed to treat and reduction of outcomes with RAAS inhibitors, European Heart Journal, Volume 34, Issue suppl_1, 1 August 2013, 5963, https://doi.org/10.1093/eurheartj/eht311.5963
Ramipril NNT to prevent a stroke = 67
Badrinath P. Preventing stroke with ramipril. Results should have been presented in ways that help practising clinicians. BMJ. 2002 Aug 24;325(7361):439. PMID: 12193364; PMCID: PMC1123947.
1991 – treatment = chlorthalidone, 12.5 mg/d. The 5-year average systolic blood pressure was 155 mm Hg for the placebo group and 143 mm Hg for the treatment group, and the average diastolic BP was 72 and 68 mm Hg, respectively. The 5-year incidence of total stroke was 5.2 per 100 participants for active treatment and 8.2 per 100 for placebo.
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 Jun 26;265(24):3255-64. PMID: 2046107.
1993 – Monotherapy with either (2) chlorthalidone (n = 136); (3) acebutolol (n = 132); (4) doxazosin mesylate (n = 134); (5) amlodipine maleate (n = 131); or (6) enalapril maleate (n = 135) was better than (1) placebo (n = 234). The SBP was reduced by 15.9 mmHg on average in the treatment arms compared to 9.1 mmHg in the lifestyle advice arm. 12.3 vs 8.6 mmHg reduction for diastolic blood pressure. And there was no significant difference between the treatment groups.
Neaton JD, Grimm RH Jr, Prineas RJ, Stamler J, Grandits GA, Elmer PJ, Cutler JA, Flack JM, Schoenberger JA, McDonald R, et al. Treatment of Mild Hypertension Study. Final results. Treatment of Mild Hypertension Study Research Group. JAMA. 1993 Aug 11;270(6):713-24. PMID: 8336373.
1998 - Captopril and atenolol were equally effective in reducing blood pressure to a mean of 144/83 mm Hg and 143/81 mm Hg respectively, with a similar proportion of patients (27% and 31%) requiring three or more antihypertensive treatments. Captopril and atenolol were equally effective in reducing the risk of macrovascular end points.
UK Prospective Diabetes Study Group. 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 Sep 12;317(7160):713-20. PMID: 9732338; PMCID: PMC28660.
2002 - Ramipril was more effective compared to amlodipine in slowing decline in GFR in African Americans with CKD. Superiority of Ramipril over Metoprolol was just marginal.
Wright JT Jr, Bakris G, Greene T, Agodoa LY, Appel LJ, Charleston J, Cheek D, Douglas-Baltimore JG, Gassman J, Glassock R, Hebert L, Jamerson K, Lewis J, Phillips RA, Toto RD, Middleton JP, Rostand SG; African American Study of Kidney Disease and Hypertension Study Group. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. JAMA. 2002 Nov 20;288(19):2421-31. doi: 10.1001/jama.288.19.2421. Erratum in: JAMA. 2006 Jun 21;295(23):2726. PMID: 12435255.
2003 – ACEi prevent more CHD and stroke deaths than diuretics as first-line treatment despite each reducing the BP a similar amount.
Wing LM, Reid CM, Ryan P, Beilin LJ, Brown MA, Jennings GL, Johnston CI, McNeil JJ, Macdonald GJ, Marley JE, Morgan TO, West MJ; Second Australian National Blood Pressure Study Group. A comparison of outcomes with angiotensin-converting--enzyme inhibitors and diuretics for hypertension in the elderly. N Engl J Med. 2003 Feb 13;348(7):583-92. doi: 10.1056/NEJMoa021716. PMID: 12584366.
2005 - CCB with addition of ACEI gives much better outcome than older regimen of beta blocker and thiazide.
Dahlöf B, Sever PS, Poulter NR, Wedel H, Beevers DG, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O'Brien E, Ostergren J; 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 Sep 10-16;366(9489):895-906. doi: 10.1016/S0140-6736(05)67185-1. PMID: 16154016.
2008 - ACEI and CCB combination was superior to the ACEI and diuretic
Jamerson K, Weber MA, Bakris GL, Dahlöf B, Pitt B, Shi V, Hester A, Gupte J, Gatlin M, Velazquez EJ; ACCOMPLISH Trial Investigators. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med. 2008 Dec 4;359(23):2417-28. doi: 10.1056/NEJMoa0806182. PMID: 19052124.
What are the major studies in this field?
1958 - FREIS ED, WANKO A, WILSON IM, PARRISH AE. Treatment of essential hypertension with chlorothiazide (diuril); its use alone and combined with other antihypertensive agents. J Am Med Assoc. 1958 Jan 11;166(2):137-40. doi: 10.1001/jama.1958.02990020025004. PMID: 13491319.
1961 - Kannel WB, Dawber TR, Kagan A, Revotskie N, Stokes J. Factors of risk in the development of coronary heart disease—six-year follow-up experience: the Framingham Study. Ann Intern Med. 1961;55:33-50
1964 - Effects of treatment on morbidity in hypertension. II. Results in patients with diastolic blood pressure averaging 90 through 114 mm Hg. JAMA. 1970 Aug 17;213(7):1143-52. PMID: 4914579.
1967 - Effects of treatment on morbidity in hypertension. Results in patients with diastolic blood pressures averaging 115 through 129 mm Hg. JAMA. 1967 Dec 11;202(11):1028-34. PMID: 4862069.
1969 - Kannel WB, Schwartz MJ, McNamara PM. Blood pressure and risk of coronary heart disease: the Framingham study. Dis Chest. 1969 Jul;56(1):43-52. doi: 10.1378/chest.56.1.43. PMID: 5789839.
1970 - Kannel WB, Wolf PA, Verter J, McNamara PM. Epidemiologic assessment of the role of blood pressure in stroke. The Framingham study. JAMA. 1970 Oct 12;214(2):301-10. PMID: 5469068.
1970 - Colandrea MA, Friedman GD, Nichaman MZ, Lynd CN. Systolic hypertension in the elderly. An epidemiologic assessment. Circulation. 1970 Feb;41(2):239-45. doi: 10.1161/01.cir.41.2.239. PMID: 5412985.
1971 - Ostfeld AM, Shekelle RB, Tufo HM, Wieland AM, Kilbridge JA, Drori J, Klawans H. Cardiovascular and cerebrovascular disease in an elderly poor urban population. Am J Public Health. 1971 Jan;61(1):19-29. doi: 10.2105/ajph.61.1.19. PMID: 5539847; PMCID: PMC1530613.
1977 - Booth J. A short history of blood pressure measurement. Proc R Soc Med. 1977 Nov;70(11):793-9. PMID: 341169; PMCID: PMC1543468.
1979 - 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 Dec 7;242(23):2562-71. PMID: 490882.
1982 - Multiple risk factor intervention trial. Risk factor changes and mortality results. Multiple Risk Factor Intervention Trial Research Group. JAMA. 1982 Sep 24;248(12):1465-77. PMID: 7050440.
1985 - MRC trial of treatment of mild hypertension: principal results. Medical Research Council Working Party. Br Med J (Clin Res Ed). 1985 Jul 13;291(6488):97-104. doi: 10.1136/bmj.291.6488.97. PMID: 2861880; PMCID: PMC1416260.
1986 - Amery A, Birkenhäger W, Brixko P, Bulpitt C, Clement D, de Leeuw P, de Plaen JF, Deruyttere M, De Schaepdryver A, Dollery C, et al. Influence of antihypertensive drug treatment on morbidity and mortality in patients over the age of 60 years. European Working Party on High blood pressure in the Elderly (EWPHE) results: sub-group analysis on entry stratification. J Hypertens Suppl. 1986 Dec;4(6):S642-7. PMID: 3475430.
1990 - Freis ED. Reminiscences of the Veterans Administration trial of the treatment of hypertension. Hypertension. 1990 Oct;16(4):472-5. doi: 10.1161/01.hyp.16.4.472. PMID: 2210815.
1991 - Esunge PM. From blood pressure to hypertension: the history of research. J R Soc Med. 1991 Oct;84(10):621. doi: 10.1177/014107689108401019. PMID: 1744849; PMCID: PMC1295564.
1991 - 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 Jun 26;265(24):3255-64. PMID: 2046107.
1992 - Neaton JD, 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 Jan;152(1):56-64. PMID: 1728930.
1993 - Neaton JD, Grimm RH Jr, Prineas RJ, Stamler J, Grandits GA, Elmer PJ, Cutler JA, Flack JM, Schoenberger JA, McDonald R, et al. Treatment of Mild Hypertension Study. Final results. Treatment of Mild Hypertension Study Research Group. JAMA. 1993 Aug 11;270(6):713-24. PMID: 8336373.
1997 - Appel LJ, Moore TJ, Obarzanek E, Vollmer WM, Svetkey LP, Sacks FM, Bray GA, Vogt TM, Cutler JA, Windhauser MM, Lin PH, Karanja N. A clinical trial of the effects of dietary patterns on blood pressure. DASH Collaborative Research Group. N Engl J Med. 1997 Apr 17;336(16):1117-24. doi: 10.1056/NEJM199704173361601. PMID: 9099655.
1997 - Cappuccio FP, Markandu ND, Carney C, Sagnella GA, MacGregor GA. Double-blind randomised trial of modest salt restriction in older people. Lancet. 1997 Sep 20;350(9081):850-4. doi: 10.1016/S0140-6736(97)02264-2. PMID: 9310603.
1998 - Hansson L, Zanchetti A, Carruthers SG, Dahlöf B, Elmfeldt D, Julius S, Ménard J, Rahn KH, Wedel H, Westerling S. 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 Jun 13;351(9118):1755-62. doi: 10.1016/s0140-6736(98)04311-6. PMID: 9635947.
1998 - UK Prospective Diabetes Study Group. 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 Sep 12;317(7160):713-20. PMID: 9732338; PMCID: PMC28660.
2002 - Wright JT Jr, Bakris G, Greene T, Agodoa LY, Appel LJ, Charleston J, Cheek D, Douglas-Baltimore JG, Gassman J, Glassock R, Hebert L, Jamerson K, Lewis J, Phillips RA, Toto RD, Middleton JP, Rostand SG; African American Study of Kidney Disease and Hypertension Study Group. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. JAMA. 2002 Nov 20;288(19):2421-31. doi: 10.1001/jama.288.19.2421. Erratum in: JAMA. 2006 Jun 21;295(23):2726. PMID: 12435255.
2002 - ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002 Dec 18;288(23):2981-97. doi: 10.1001/jama.288.23.2981. Erratum in: JAMA 2003 Jan 8;289(2):178. Erratum in: JAMA. 2004 May 12;291(18):2196. PMID: 12479763.
2002 - Lewington S, Clarke R, Qizilbash N, Peto R, Collins R; Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002 Dec 14;360(9349):1903-13. doi: 10.1016/s0140-6736(02)11911-8. Erratum in: Lancet. 2003 Mar 22;361(9362):1060. PMID: 12493255.
26. 2003 - Wing LM, Reid CM, Ryan P, Beilin LJ, Brown MA, Jennings GL, Johnston CI, McNeil JJ, Macdonald GJ, Marley JE, Morgan TO, West MJ; Second Australian National Blood Pressure Study Group. A comparison of outcomes with angiotensin-converting--enzyme inhibitors and diuretics for hypertension in the elderly. N Engl J Med. 2003 Feb 13;348(7):583-92. doi: 10.1056/NEJMoa021716. PMID: 12584366.
27. 2003 - Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ; Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. National Heart, Lung, and Blood Institute; National High Blood Pressure Education Program Coordinating Committee. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003 Dec;42(6):1206-52. doi: 10.1161/01.HYP.0000107251.49515.c2. Epub 2003 Dec 1. PMID: 14656957.
28. 2005 - Dahlöf B, Sever PS, Poulter NR, Wedel H, Beevers DG, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O'Brien E, Ostergren J; 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 Sep 10-16;366(9489):895-906. doi: 10.1016/S0140-6736(05)67185-1. PMID: 16154016.
2008 - Beckett NS, Peters R, Fletcher AE, Staessen JA, Liu L, Dumitrascu D, Stoyanovsky V, Antikainen RL, Nikitin Y, Anderson C, Belhani A, Forette F, Rajkumar C, Thijs L, Banya W, Bulpitt CJ; HYVET Study Group. Treatment of hypertension in patients 80 years of age or older. N Engl J Med. 2008 May 1;358(18):1887-98. doi: 10.1056/NEJMoa0801369. Epub 2008 Mar 31. PMID: 18378519.
2008 - Jamerson K, Weber MA, Bakris GL, Dahlöf B, Pitt B, Shi V, Hester A, Gupte J, Gatlin M, Velazquez EJ; ACCOMPLISH Trial Investigators. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med. 2008 Dec 4;359(23):2417-28. doi: 10.1056/NEJMoa0806182. PMID: 19052124.
2008 - D'Agostino RB Sr, Vasan RS, Pencina MJ, Wolf PA, Cobain M, Massaro JM, Kannel WB. General cardiovascular risk profile for use in primary care: the Framingham Heart Study. Circulation. 2008 Feb 12;117(6):743-53. doi: 10.1161/CIRCULATIONAHA.107.699579. Epub 2008 Jan 22. PMID: 18212285.
2008 – (ACCORD) The Action to Control Cardiovascular Risk in Diabetes Study Group Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545–2559. doi: 10.1056/NEJMoa0802743.
2008 - Kannel WB, Wolf PA. Framingham Study insights on the hazards of elevated blood pressure. JAMA. 2008 Dec 3;300(21):2545-7. doi: 10.1001/jama.2008.759. PMID: 19050198.
2010 - ACCORD Study Group, Cushman WC, Evans GW, Byington RP, Goff DC Jr, Grimm RH Jr, Cutler JA, Simons-Morton DG, Basile JN, Corson MA, Probstfield JL, Katz L, Peterson KA, Friedewald WT, Buse JB, Bigger JT, Gerstein HC, Ismail-Beigi F. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010 Apr 29;362(17):1575-85. doi: 10.1056/NEJMoa1001286. Epub 2010 Mar 14. PMID: 20228401; PMCID: PMC4123215.
2014 - Mahmood SS, Levy D, Vasan RS, Wang TJ. The Framingham Heart Study and the epidemiology of cardiovascular disease: a historical perspective. Lancet. 2014 Mar 15;383(9921):999-1008. doi: 10.1016/S0140-6736(13)61752-3. Epub 2013 Sep 29. PMID: 24084292; PMCID: PMC4159698.
2015 - SPRINT Research Group, Wright JT Jr, Williamson JD, Whelton PK, Snyder JK, Sink KM, Rocco MV, Reboussin DM, Rahman M, Oparil S, Lewis CE, Kimmel PL, Johnson KC, Goff DC Jr, Fine LJ, Cutler JA, Cushman WC, Cheung AK, Ambrosius WT. A Randomized Trial of Intensive versus Standard Blood-Pressure Control. N Engl J Med. 2015 Nov 26;373(22):2103-16. doi: 10.1056/NEJMoa1511939. Epub 2015 Nov 9. Erratum in: N Engl J Med. 2017 Dec 21;377(25):2506. PMID: 26551272; PMCID: PMC4689591.
2016 - Saklayen MG, Deshpande NV. Timeline of History of Hypertension Treatment. Front Cardiovasc Med. 2016 Feb 23;3:3. doi: 10.3389/fcvm.2016.00003. PMID: 26942184; PMCID: PMC4763852.
2018 - Estruch R, Ros E, Salas-Salvadó J, Covas MI, Corella D, Arós F, Gómez-Gracia E, Ruiz-Gutiérrez V, Fiol M, Lapetra J, Lamuela-Raventos RM, Serra-Majem L, Pintó X, Basora J, Muñoz MA, Sorlí JV, Martínez JA, Fitó M, Gea A, Hernán MA, Martínez-González MA; PREDIMED Study Investigators. Primary Prevention of Cardiovascular Disease with a Mediterranean Diet Supplemented with Extra-Virgin Olive Oil or Nuts. N Engl J Med. 2018 Jun 21;378(25):e34. doi: 10.1056/NEJMoa1800389. Epub 2018 Jun 13. PMID: 29897866.