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Clinical Medicine: Landmark Papers

Papers that Changed Practice

Landmark Papers

ALLHAT. 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;288(23):2981-2997.

Arguedas JA, Leiva V, Wright JM. Blood pressure targets for hypertension in people with diabetes mellitus. Cochrane Database Syst Rev. 2013.  

Benavente OR, Coffey CS, Conwit R, et al. Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial. Lancet. 2013: 382(9891):507-15.

Cooper CJ, Murphy TP, Cutlip DE, et al. Stenting and medical therapy for atherosclerotic renal-artery stenosis. N Engl J Med. 2014: 370(1):13-22

Gerstein HC, Miller ME, Genuth S et al. Long-term effects of intensive glucose lowering on cardiovascular outcomes. N Engl J Med 2011;364(9):818-828.

Hansson L, Zanchetti A, Carruthers SG et al. 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(9118):1755-1762.

Hypertension Detection and Follow-up Program Cooperative Group. 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(5):633-638. PMID: 7033578

Jamerson K, Weber MA, Bakris GL, et al.  Benazepril plus Amlodipine or Hydrochlorothiazide for Hypertension in High-Risk Patients.  Am J Card. 2013: 112(2): 255-259.  

Pedrosa RP, Drager LF, de Paula LK, et al. Effects of OSA treatment on BP in patients with resistant hypertension: a randomized trial. Chest. 2013: 144(5):1487-94.  

Ruggenenti P, Perna A, Loriga G et al. Blood-pressure control for renoprotection in patients with non-diabetic chronic renal disease (REIN-2): multicentre, randomised controlled trial. Lancet 2005;365(9463):939-946.

Stergiou GS, Bliziotis IA.. Home blood pressure monitoring in the diagnosis and treatment of hypertension: a systematic review. Am J Hypertens 2011;24(2):123-134.

Tinetti ME, Han L, Lee DS, et al.  Antihypertensive Medications and Serious Fall Injuries in a Nationally Representative Sample of Older Adults.  JAMA Intern Med. 2014;174(4):588-595.  

Verdecchia P, Porcellati C, Schillaci G et al. Ambulatory blood pressure. An independent predictor of prognosis in essential hypertension. Hypertension 1994;24(6):793-801.



Commit.  Early intravenous then oral metoprolol in 45 852 patients with acute myocardial infarction: randomised placebo-controlled trial.  The Lancet. 2005:  366(9497):1622-1632.  

Connolly SJ, Ezekowitz MD, Phil D, et al. Dabigatran versus Warfarin in Patients with Atrial Fibrillation.  N Engl J Med 2009; 361:1139-1151.

The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997; 336:525-533

Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Volume 355, Issue 9200, 22 January 2000, Pages 253–259

Hylek EM, Held C, Alexander JH, et al. Major Bleeding in Patients With Atrial Fibrillation Receiving Apixaban or Warfarin: The ARISTOTLE Trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation): Predictors, Characteristics, and Clinical Outcomes. J Am Coll Cardiol. 2014;63(20):2141-7.  

ISIS-2 Collaborative Group.  Randomised Trial of Intravenous Streptokinase, Oral Aspirin, Both, or Neither among 17187 Cases of Suspected Acute Myocardial Infarction. The Lancet 1988.: 332(8607):349-360.

Lee CW, Ahn JM, Park DW, et al. Optimal duration of dual antiplatelet therapy after drug-eluting stent implantation: a randomized, controlled trial. Circulation. 2014 : 129(3):304-12.

Leon MB, Smith CR, Mack M, et al.  Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery.  N Engl J Med 2010; 363:1597-1607.  

Lewis HD, Davis JW, Archibald DG, et al. Protective Effects of Aspirin against Acute Myocardial Infarction and Death in Men with Unstable Angina — Results of a Veterans Administration Cooperative Study.   N Engl J Med 1983; 309:396-403.  

Matulevicius S, Rohatgi A, Das SR, et al. Appropriate Use and Clinical Impact of Transthoracic Echocardiography.  JAMA Intern Med. 2013;173(17):1600-1607.

Pitt B, Pfeffer MA, Assmann SF, et al. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. 2014: 370(15): 1383-1392.  

Pitt et al. for the Randomized Aldactone Evaluation Study Investigators. The effect of Spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999; 341:709-717.

Poole-Wilson et al, for the COMET investigators, Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial, The Lancet, Volume 362, Issue 9377, 5 July 2003, Pages 7-13.

Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomized trials. The Lancet  2014;383(9921): 955-962.  

The Heart Outcomes Prevention Evaluation Study Investigators.  Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients.  N Engl J Med 2000; 342: 145-153.  

Van Gelder et al. Lenient versus strict rate control in patients with atrial fibrillation. N Engl J Med 2010; 362:1363-1373

Young et al. for the Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) Investigators and Committees. Mortality and morbidity reduction with Candesartan in patients with chronic heart failure and left ventricular systolic dysfunction: Results of the CHARM Low-Left Ventricular Ejection Fraction Trials. Circulation. 2004; 110: 2618-2626

Critical Care

Caironi P, Tognoni G, Masson S, et al. Albumin replacement in patients with severe sepsis or septic shock. N Engl J Med. 2014: 370(15):1412-21.

Gray A, Goodacre S, Newby DE, et al. Noninvasive Ventilation in Acute Cardiogenic Pulmonary Edema.  N Engl J Med 2008;359:142-51.  

Lamontagne F, McIntyre L, Dodek P, et al. Nonleg Venous Thrombosis in Critically Ill Adults A Nested Prospective Cohort Study.  JAMA 2014: 174(5): 689-696. 

The NICE-SUGAR Study Investigators.  Hypoglycemia and Risk of Death in Critically Ill Patients. N Engl J Med 2012;367:1108-18.   

Van den Berghe G, Wilmer A, Hermans G, et al.   Intensive Insulin Therapy in the Medical ICU.  N Engl J Med 2006;354:449-61.  

Young et al. High frequency oscillatory ventilation does not improve outcomes compared to conventional ventilation in early ARDS. NEJM 2013; 368; 806-813.


Farsaei S, Khalili H, Farboud ES, et al. Efficacy of topical atorvastatin for the treatment of pressure ulcers: a randomized clinical trial. Pharmacotherapy. 2014: 34(1):19-27.  


Duckworth W, Abaira C, Moritz T, et al.  Glucose Control and Vascular Complications in Veterans with Type 2 Diabetes.  N Engl J Med 2009; 360:129-139.  

Hemmingsen B, Lund SS, Gluud C, et al. Targeting intensive glycaemic control versus targeting conventional glycaemic control for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2013 Nov: 1-380.

Perkovic V, Heerspink HL, Chalmers J, et al. Intensive glucose control improves kidney outcomes in patients with type 2 diabetes. Kidney Int. 2013: 83(3):517-23.   

Shah B, Berger JS, Amoroso NS, et al. Periprocedural glycemic control in patients with diabetes mellitus undergoing coronary angiography with possible percutaneous coronary intervention. Am J Cardiol. 2014: 113(9): 1474-1480.  

Sharma A, Chatterjee S, Arbab-Zadeh A, et al. Risk of serious atrial fibrillation and stroke with use of bisphosphonates: evidence from a meta-analysis. Chest. 2013 :144(4):1311-22.

The ACCORD Study Group. Effects of Intensive Blood-Pressure Control in Type 2 Diabetes Mellitus.  N Engl J Med 2010; 362:1575-1585.   

The ADVANCE Collaborative Group.  Intensive Blood Glucose Control and Vascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med 2008;358:2560-72. 

Theodoratou E, Tzoulaki I, Zgaga L, et al. Vitamin D and multiple health outcomes: umbrella review of systematic reviews and meta-analyses of observational studies and randomised trials.  BMJ 2014: 348 (2035): 1-19.  

UK Prospective Diabetes Study Group.  Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes:  UKPDS 38.  BMJ 1998: 317: 703.  

End of Life Care

Ebell MH, Jang W, Shen Y, et al. Development and validation of the Good Outcome Following Attempted Resuscitation (GO-FAR) score to predict neurologically intact survival after in-hospital cardiopulmonary resuscitation. JAMA Intern Med. 2013 ;173(20):1872-8.


Briasoulis A, Agarwal V, Tousoulis D, et al. Effects of antihypertensive treatment in patients over 65 years of age: a meta-analysis of randomised controlled studies. Heart. 2014: 100(4):317-23.  

Hatta K, Kishi Y, Wada K, et al. Preventive effects of ramelteon on delirium: a randomized placebo-controlled trial. JAMA Psychiatry. 2014: 71(4):397-403.

Wang, et al. Prazosin for the Treatment of Behavioral Symptoms in Patients With Alzheimer Disease With Agitation and Aggression, The American Journal of Geriatric Psychiatry, Volume 17, Issue 9, September 2009, Pages 744-751.


Somatostatin analogues for acute variceal bleeding (Cochrane review 2005)


Colombel JF, Sandborn WJ, Reinisch W et al.  Infliximab, azathioprine, or combination therapy for Crohn's disease. N Engl J Med. 2010;362(15):1383-95. 

Drekonja DM, Butler M, MacDonald R, Bliss D, Filice GA, Rector TS, and Wilt TJ. Comparative Effectiveness of Clostridium difficile Treatments: A Systematic Review. Annals of Internal Medicine 2011; 155(12): 839-847.  

Wang J, Bao YX, Bai M, Zhang YG, Xu WD, and Qi XS. Restrictive vs. liberal transfusion for upper gastrointestinal bleeding: a meta-analysis of randomized controlled trials. World Journal of Gastroenterology 2013; 19(40): 6919-6927.   

Zuezem S, Dusheiko GM, Salupere R, Mangia A, Flisiak R, Hyland RH, et al. Sofosbuvir and ribavirin in HCV genotypes 2 and 3. New England Jeournal of Medicine 2014; 370(21): 1993-2001.

Hematology VTE

Brighton TA, Eikelboom, JW, Mann K, et al. Low-Dose Aspirin for Preventing Recurrent Venous Thromboembolism N Engl J Med 2012; 367:1979-1987.  

Granger CB, Alexander JH, McMurray JJV, et alApixaban versus Warfarin in Patients with Atrial Fibrillation.  N Engl J Med 2011; 365:981-992.  

Lee et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003; 349:146-153

Schulman S, Kakkar AK, Goldhaber SZ, et al. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014: 129(7):764-72.


Houle et al (2012). The 2012-2013 Canadian Hypertension Education Program (CHEP) guidelines for pharmacistsCanadian Pharmacists Journal / Revue des Pharmaciens du Canada May/June 2013 vol. 146 no. 3 146-150


Dimopoulos G, Poulakou G, Pneumatikos IA et al. Short- vs long-duration antibiotic regimens for ventilator-associated pneumonia: A systematic review and meta-analysis. Chest 2013: 144(6): 1745-1767.


Allen RP, Chen C, Garcia-Borreguero D, et al. Comparison of pregabalin with pramipexole for restless legs syndrome. N Engl J Med. 2014: 370(7):621-31.

Gouya G, Arrich J, Wolzt M, et al. Antiplatelet treatment for prevention of cerebrovascular events in patients with vascular diseases: a systematic review and meta-analysis. Stroke. 2014: 45(2): 492-503.

Halvorsen S, Atar D, Yang H, et al. Efficacy and safety of apixaban compared with warfarin according to age for stroke prevention in atrial fibrillation: observations from the ARISTOTLE trial. Eur Heart J. 2014: 1-9.  

Lee HY, Byun JY, Park MS, et al. Steroid-antiviral treatment improves the recovery rate in patients with severe Bell`s palsy. Am J Med. 2013: 126(4):336-4.


Bart et al. Ultrafiltration in decompensated heart failure with cardiorenal syndrome. N Engl J Med 2012; 367:2296-2304

Hofstra JM, Beck Jr LH, Beck DM, Wetzels JF, and Salant DJ. Anti-Phospholipase A2 Receptor Antibodies Correlate with Clinical Status in Idiopathic Membranous Nephropathy. CJASN 2011;  6(6): 1286-1291.

Leoncini M, Toso A, Maioli M, et al. Early high-dose rosuvastatin for contrast-induced nephropathy prevention in acute coronary syndrome: Results from the PRATO-ACS Study (Protective Effect of Rosuvastatin and Antiplatelet Therapy On contrast-induced acute kidney injury and myocardial damage in patients with Acute Coronary Syndrome). J Am Coll Cardiol. 2014: 63(1):71-79.

Tonelli M, Wiebe N, Culleton B, House A, Rabbat C, Fok M, McAlister F, and Garg, AX. Chronic Kidney Disease and Mortality Risk: A Systemic Review. Journal of the American Society of Nephrology 2006; 17: 2034-2047.


The Idiopathic Pulmonary Fibrosis Clinical Research Network. Prednisone, azithromycin, NAC for idiopathic pulmonary fibrosis. NEJM. 2012;366;1968-1977.

Leuppi JD, Schuetz P, Bingisser R et al.  Short-term vs conventional glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: the REDUCE randomized clinical trial.  JAMA. 2013;309(21):2223-31.

Leuppi JD, Schuetz P, Bingisser R, et al. Short-term vs conventional glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: the REDUCE randomized clinical trial. JAMA. 2013: 309(21):2223-31.

Suissa S, Patenaude V, Lapi F, et al. Inhaled corticosteroids in COPD and the risk of serious pneumonia. Thorax. 2013: 68(11):1029-36.  

Kannel WB, Castelli WP, Gordon T.. Cholesterol in the prediction of atherosclerotic disease. New perspectives based on the Framingham study. Ann Intern Med 1979;90(1):85-91.

Assmann G, Schulte H.. Relation of high-density lipoprotein cholesterol and triglycerides to incidence of atherosclerotic coronary artery disease (the PROCAM experience). Prospective Cardiovascular Munster study. Am J Cardiol 1992;70(7):733-737.

The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease. JAMA 1984;251(3):351-364.  PMID: 6361299

Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344(8934):1383-1389.

Downs JR, Clearfield M, Weis S et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998;279(20):1615-1622.

LaRosa JC, Grundy SM, Waters DD et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005;352(14):1425-1435.

Ridker PM, Danielson E, Fonseca FA et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359(21):2195-2207.

Bulbulia R, Bowman L, Wallendszus K et al. Effects on 11-year mortality and morbidity of lowering LDL cholesterol with simvastatin for about 5 years in 20,536 high-risk individuals: a randomised controlled trial. Lancet 2011;378(9808):2013-2020.

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