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Clin J Am Soc Nephrol 3: S11-S16, 2008
© 2008 American Society of Nephrology
doi: 10.2215/CJN.03260807
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Article

Stroke in Chronic Kidney Disease: Prevention and Management

Raymond R. Townsend

Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

Correspondence: Dr. Raymond Townsend, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104. Phone: 215-662-4630; Fax: 215-662-3459; E-mail: townsend{at}mail.med.upenn.edu


   Abstract
Top
 Abstract
Introduction
 Assessing Stroke Risk in...
 Preventing Stroke
 Acute Management of BP...
 Conclusions
 Disclosures
 References
 
The incidence of stroke is elevated among individuals with kidney disease. Traditional risk factors seem to account for much but not all of this excess risk. Blood pressure control is the most important aspect of stroke prevention. Multiple classes of antihypertensive agents, including diuretics, calcium channel blockers, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers, have reduced stroke risk. Some physiologic and clinical evidence suggests that angiotensin II receptor blockers may offer superior benefit to that of angiotensin-converting enzyme inhibitors for the same level of blood pressure control; however, few head-to-head trials have compared these two agent classes directly using stroke as an outcome.


   Introduction
Top
 Abstract
 Introduction
Assessing Stroke Risk in...
 Preventing Stroke
 Acute Management of BP...
 Conclusions
 Disclosures
 References
 
The content is based on an official American Society of Nephrology continuing medical education luncheon symposium held November 16, 2006, in San Diego, California.

Faculty:

George L. Bakris, MD, Hypertensive Diseases Unit, Section of Endocrinology, Diabetes and Metabolism, Pritzker School of Medicine, University of Chicago, Chicago, Illinois

Stuart L. Linas, MD, Department of Internal Medicine, Division of Renal Diseases and Hypertension, University of Colorado Health Sciences Center, Denver, Colorado

Raymond R. Townsend, MD, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

Credit Designation Statement: The American Society of Nephrology designates this educational activity (entire supplement) for a maximum of 2.0 AMA PRA Category 1 CreditsTM. Physicians should only claim credit commensurate with the extent of their participation in the activity. Study the education content, and complete the examination; 80% correct is required for full credit on first submission. Continuing medical education credit eligible through November 2008.

Learning Objectives:

  1. To examine the epidemiology and pathophysiology of stroke and cardiovascular disease in the chronic kidney disease population
  2. To evaluate the efficacy of current therapies for the treatment of cardiovascular risk in patients with renal disease
  3. To apply new clinical insights for the identification and treatment of cardiovascular risk to improve outcomes for patients with chronic kidney disease

Target audience: Physicians in internal medicine, nephrology, endocrinology, and other health care providers who are interested in the treatment of hypertension and kidney disease.

Categories: Stroke prevention, angiotensin receptor blocker, angiotensin-converting enzyme inhibitor, kidney disease

High BP and kidney disease have been associated with increased incidence of stroke (1). BP control is crucial to stroke prevention (2). Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB), among other antihypertensive agents, have demonstrated effectiveness in reducing stroke risk (3). This article reviews stroke prevention as well as acute stroke management in patients with kidney disease.


   Assessing Stroke Risk in Individuals with Renal Disease
Top
 Abstract
 Introduction
 Assessing Stroke Risk in...
Preventing Stroke
 Acute Management of BP...
 Conclusions
 Disclosures
 References
 
In another article in this supplement, Bakris et al. summarize epidemiologic data documenting an association between kidney function and stroke risk (1,4,5). Evaluating stroke risk in individuals with kidney disease involves much the same process as in other populations because the same risk factors apply (Table 1) (2,6). Patients should be assessed for the presence of risk factors listed in Table 1, as well as for type of renal disease and estimated GFR.


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  		Table 1. Risk factors for strokea

 
Traditional risk factors account for much but not all of the excess stroke risk in chronic kidney disease (CKD). Epidemiologic studies report an elevated stroke risk in kidney disease after adjustment for such factors (where kidney function is usually stated as an estimated GFR <60 ml/min per 1.73 m2 or a serum creatinine >1.3 mg/dl) (4,5,7,8). Physiologic evidence also suggests that renal impairment itself in some way increases susceptibility to stroke. The proportionate contribution of traditional risk factors and the CKD milieu to stroke risk is unclear. Modifiable risk factors should be identified and addressed.

Those at elevated risk for intracranial aneurysm can be evaluated through noninvasive imaging. Counseling patients in advance about the implications of detection on driver's licensing, life insurance, and other issues is advisable (9).


   Preventing Stroke
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 Abstract
 Introduction
 Assessing Stroke Risk in...
 Preventing Stroke
Acute Management of BP...
 Conclusions
 Disclosures
 References
 
Several approaches to primary and secondary stroke prevention have been explored in the literature, including the treatment of dyslipidemia and anemia, BP control, and the use of ARB outside of BP control. The current evidence and the merit of these approaches are discussed here in the context of stroke and cardiovascular disease (CVD) risk and prevention.

Treating Dyslipidemia
Some data suggest that reduction of LDL cholesterol may be beneficial in secondary prevention of CVD, although not of stroke, among individuals with reduced kidney function. A post hoc subgroup analysis of patients with chronic renal insufficiency (creatinine clearance ≤75 ml/min) in the Cholesterol and Recurrent Events (CARE) trial indicated that pravastatin was associated with a lower incidence of the combined primary outcome (death from coronary disease or symptomatic nonfatal myocardial infarction [MI]) compared with placebo after a median follow-up of nearly 5 yr (adjusted hazard ratio [HR] 0.72; 95% confidence interval [CI] 0.55 to 0.95; P = 0.02) (10).

Patients (n = 1711) also had a history of MI and total plasma cholesterol <240 mg/dl. Reduction of stroke risk, a secondary end point, did not reach significance (adjusted HR 0.62; 95% CI 0.39 to 1.00; P = 0.051) (10). The ongoing Study of Heart and Renal Protection (SHARP), which included roughly 9,000 patients with CKD and evaluated the effects of simvastatin plus ezetimibe, should provide more information about lipid reduction and prevention of vascular events in kidney disease (11).

Addressing Anemia
Anemia has been shown to substantially increase the risk for stroke associated with CKD (7). Recombinant erythropoietin is indicated to correct this condition in individuals with CKD (12). A 2006 update of National Kidney Foundation guidelines defined target hemoglobin as ≥11.0 g/dl and advised caution when intentionally maintaining hemoglobin at >13.0 g/dl (13). A clinical trial published at the end of 2006 underscores the risk of a higher target hemoglobin level. The Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) investigators concluded that a hemoglobin target of 13.5 g/dl was associated with significantly greater risk for the primary composite outcome (death, MI, hospitalization for congestive heart failure without renal replacement therapy, or stroke) compared with a lower target of 11.3 g/dl (HR 1.34; 95% CI 1.03 to 1.74; P = 0.03) (14). This increased risk was associated with a lower-than-targeted hemoglobin level, as the mean achieved hemoglobin value in the higher target group was 12.6 g/dl (14). Patients in the higher target group received nearly twice the amount of epoetin {alpha} as those in the lower target group (mean 11,215 versus 6276 U/wk, respectively) (14). Quality-of-life improvements were similar in both treatment groups (14). More patients in the higher target group had at least one serious adverse event (14). It may be that the small BP increase noted with erythropoietin, the lessened bleeding tendency when hematocrit is raised (thus a greater thrombosis potential), the increase in the viscosity of blood when hematocrit is higher, and the potential oxidative stress that is induced by greater iron administration may have contributed to these findings (15). The authors therefore recommended a hemoglobin target of 11.0 to 12.0 g/dl in patients with CKD (15 to 50 ml/min per 1.73 m2 in their study) (14).

BP Control
Good BP control is the most important factor in stroke prevention irrespective of the antihypertensive agent used (16). Rapid control of BP, within weeks rather than months, is an important factor in CV risk reduction, at least in hypertensive patients at high CV risk (17).

ACEI, ARB, and calcium channel blockers (CCB) have significantly reduced stroke risk in clinical trials (3). The Blood Pressure Lowering Treatment Trialists’ Collaboration's prospective analyses of data from 29 randomized studies (n = 162,341) concluded in part that treatment with ACEI- or CCB-based regimens significantly lowered stroke risk compared with placebo and that ARB-based treatment reduced stroke risk compared with control regimens. Lower BP goals also resulted in greater decreases in stroke risk (3). Nonsignificant trends pointed to greater risk reduction with treatment based on diuretics, β blockers, and CCB compared with regimens based on ACEI (3). The investigators concluded that BP lowering is a major component of all drug classes’ effects in stroke prevention (3).

A published review of clinical trial results proposes the possibility of a superior benefit for ARB in stroke prevention in part because multiple trials of ACEI have demonstrated either no significant decrease or a significant increase in stroke risk (16,18–20) in active comparator trials. Table 2 (17–23) summarizes illustrative trials. Two of these studies cited differences in BP achieved as possible reasons for the increased stroke risk with ACEI therapy (18,19), although at least one trial reported that ACEI reduced stroke risk (21).


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  		Table 2. Effect of ACEI and ARB therapy on stroke riska

 
Multiple trials of ARB have demonstrated significant reductions in stroke risk (22,23). An exception was the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial, in which valsartan-based treatments were associated with a nonsignificant increase in stroke rate compared with amlodipine-based regimens (17). Stroke was a secondary outcome of this trial; the primary composite outcome (cardiac morbidity and mortality) did not differ significantly between groups (HR 1.04; 95% CI 0.94 to 1.15; P = 0.49) (17).

A subsequent analysis of these findings illustrated the importance of timing as well as degree of BP reduction. BP response after the first month of treatment predicted events and survival (24). Differences in BP were significant throughout the trial but especially pronounced during this period (17). At 1 mo, mean BP in patients who were randomly assigned to amlodipine-based therapy was 4.0/2.1 mmHg lower than in those who received valsartan-based treatment. The average difference narrowed to 2.1/1.6 mmHg at 6 mo and remained at roughly that level for the rest of the study (17). From 6 mo to study end (at 72 mo), BP reduction was similar: 3.0/2.5 mmHg with amlodipine-based therapy and 3.3/2.6 mmHg with valsartan-based treatment (17). Approximately 76% of the excess strokes in the valsartan group occurred during the first year of therapy, when the difference in BP was the largest (17).

ARB Benefits Beyond BP?
Physiologic findings support the hypothesis that ARB may be superior to ACEI in terms of stroke prevention for the same degree of BP control (16). Experimental evidence suggests that angiotensin II (AngII) has beneficial as well as detrimental effects on CV and cerebrovascular function. The detrimental effects from increased BP stem from AngII stimulation of the AT1 receptor, which ARB block. The beneficial actions derive from AngII stimulation of the other AngII receptor type (AT2) (16). The actions of AT1 typically dominate; however, experimental evidence indicates that selective AT1 blockade enhances the cerebroprotective effects of AT2 stimulation (16). AT1 blockade leads to upregulation of AT2 receptors in endothelial cells (16). It also leaves AngII free to stimulate the AT2 receptors (16). ACEI, in contrast, interfere with the production of AngII (16).

Certain ARB offer other cerebroprotective effects unrelated to AngII (16). Losartan interferes with platelet aggregation; increased platelet aggregation has been linked to elevated stroke risk (16). The effect of serum uric acid on stroke and CV risk has been disputed (16). In an analysis of the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study, however, baseline serum uric acid was significantly associated with CV complications. Losartan's reduction of uric acid accounted for 29% of its treatment effect on the primary composite end point (CV death, MI, or stroke) compared with atenolol (25).

The ARB telmisartan exerts beneficial effects on glucose metabolism independent of its action on the renin-angiotensin system (16). Other ARB have reduced the risk for new-onset diabetes compared with a CCB (valsartan) (17) and with a β blocker (losartan) (22). Such effects may be of interest because newly diagnosed diabetes is associated with an increased stroke risk in the first 5 yr after onset (26).


   Acute Management of BP During Ischemic Stroke
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 Abstract
 Introduction
 Assessing Stroke Risk in...
 Preventing Stroke
 Acute Management of BP...
Conclusions
 Disclosures
 References
 
Few data are available regarding BP management during acute ischemic stroke, making this a controversial issue (27,28). American Stroke Association guidelines for managing BP in patients who sustain acute ischemic stroke and are ineligible for thrombolytic therapy may seem to be counterintuitive. No pharmacologic treatment should be initiated if systolic BP (SBP) is <220 or diastolic BP (DBP) is <120 mmHg unless there is end-organ involvement (e.g., acute renal failure, acute MI) (27). BP falls spontaneously in the majority of cases, and there is little scientific basis for antihypertensive therapy (27).

Further definition of what constitutes "end-organ involvement" would aid in treatment decisions. Whether persistently elevated creatinine levels (e.g., 1.8 mg/dl) can be considered an indication to administer antihypertensive therapy for patients with lower BP, for example, remains to be clarified. Determinations must be made on a case-by-case basis. Patients with SBP of >220 or DBP of 121 to 140 mmHg should receive nicardipine or labetalol. If DBP is >140 mmHg, then nitroprusside should be administered. The goal is to lower BP by 10 to 15% (27).

Prevention of Recurrent Stroke
History of stroke confers a 20% risk for recurrent stroke within 5 yrs (29). Treatment with the ACEI perindopril and the diuretic indapamide added at the physician's discretion reduced recurrent stroke risk over 4 yrs by 28% compared with placebo (95% CI 17 to 38%; P < 0.0001; n = 6,105) (30). The risk reduction remained significant irrespective of the presence of hypertension; roughly half of patients were hypertensive (30). In the subset of patients who received combination therapy (n = 3,544, 58% of total), the risk for recurrent stroke was reduced by 43% (95% CI 30 to 54%; P < 0.001) compared with placebo (30). The effect of perindopril alone did not differ significantly from that of placebo (30). Investigators attributed this difference to the greater BP-lowering effect achieved with combination therapy (12/5 versus 5/3 mmHg) (30).

The ARB eprosartan also has significantly reduced the risk for recurrent stroke compared with nitrendipine during a median follow-up of 2.5 yrs. Outcome was calculated by including recurrent rather than only first events. The primary end point was a composite of all-cause mortality and CV and cerebrovascular events (intracerebral hemorrhage, stroke recurrence, or transient ischemic attack/prolonged reversible ischemic neurologic deficit) (31). All patients (n = 1,405) were hypertensive (31). Approximately two thirds required multiple agents for BP control; diuretics and β blockers were the most common choices (31). The eprosartan group experienced a lower incidence density per 100 patient-years of the primary outcome (13.25 versus 16.71; incidence density rate 0.79; P = 0.014). The risk for cerebrovascular events also was reduced significantly (incidence density of 6.56 versus 8.78 per 100 patient-years; incidence density rate 0.75; P = 0.026) (31). Incidence density is defined as the number of incident cases that arise in a susceptible population during a given time period; units are expressed as the number of cases per unit of person time (32).

The largest trial to evaluate recurrent stroke prevention therapy (>20,000 patients randomly assigned) is currently comparing telmisartan versus usual care while also comparing two antiplatelet therapies (aspirin plus extended-release dipyridamole versus clopidogrel). Patients in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) study are ≥50 yrs of age, present within 120 d of ischemic stroke, and stable when randomly assigned (33).

Additional information will come from the Ongoing Telmisartan Alone and in Combination with Ramipril Global End-point Trial (ONTARGET). This large (n = 25,620) trial is comparing the impact of ramipril, telmisartan, and the combination on a composite end point of CV mortality, MI, stroke, or heart failure hospitalization. Patients are ≥55 yrs of age with a history of coronary artery disease, peripheral vascular disease, cerebrovascular disease, or diabetes with end-organ damage (34). Participants will be followed for 3.5 to 5 yrs (34).

A similarly designed trial (Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease [TRANSCEND]) compares the effect of telmisartan and placebo on the same primary end point and in patients with the same profile as those in ONTARGET except for their intolerance of ACEI (n = 6,000) (34). Results of both trials are expected in 2008.


   Conclusions
Top
 Abstract
 Introduction
 Assessing Stroke Risk in...
 Preventing Stroke
 Acute Management of BP...
 Conclusions
Disclosures
 References
 
Kidney disease has been associated with increased stroke risk. Prevention of stroke requires aggressive management of traditional risk factors, including hypertension. Some of the excess stroke risk in individuals with renal disease seems to derive from consequences of renal impairment.

Multiple classes of antihypertensive agents reduce stroke risk. Physiologic evidence points to a basis for stroke risk reduction with ARB beyond that attributable to BP lowering. Both ACEI- and ARB-based therapies have demonstrated efficacy in reducing the risk for recurrent stroke. Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) will yield additional information about the most effective regimens for preventing recurrent stroke. The findings of ONTARGET and TRANSCEND should further clarify the role of ACEI, ARB, and the combination in risk reduction.


   Disclosures
Top
 Abstract
 Introduction
 Assessing Stroke Risk in...
 Preventing Stroke
 Acute Management of BP...
 Conclusions
 Disclosures
References
 
R.R.T. has served as a consultant to Glaxo Smith Kline, Atcor Medical, and Abbott Laboratories; has received research funding from Novartis (ACCOMPLISH trial) and National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease and honoraria from Merck, Bristol Myers Squibb, and Pfizer; and serves as associate editor of the Nephrology Self Assessment Program (NephSAP). He also discloses a financial relationship with UpToDate and PIER (ACP/ASIM).


   Acknowledgments
 
This activity is supported by an independent educational grant from Boehringer Ingelheim.

Eileen A. McCaffrey, MA, Clarus Health, provided writing support.


   Footnotes
 
Activity Production: Each author was provided with the final edited manuscript, which was transcribed by a medical writer from the author's original presentation, for final approval. The posttest questions were written on the basis of the supplement content and reviewed by the continuing medical education accreditor.


   References
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 Abstract
 Introduction
 Assessing Stroke Risk in...
 Preventing Stroke
 Acute Management of BP...
 Conclusions
 Disclosures
 References
 

  1. US Renal Data System: USRDS 2006 Annual Data Report: Atlas of End-Stage Renal Disease in the United States, Bethesda, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health,2006
  2. Goldstein LB, Adams R, Alberts MJ, Appel LJ, Brass LM, Bushnell CD, Culebras A, Degraba TJ, Gorelick PB, Guyton JR, Hart RG, Howard G, Kelly-Hayes M, Nixon JV, Sacco RL: Primary prevention of ischemic stroke: A guideline from the American Heart Association/American Stroke Association Stroke Council: Cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group: the American Academy of Neurology affirms the value of this guideline. Stroke37 :1583 –1633,2006[Abstract/Free Full Text]
  3. Turnbull F, for the Blood Pressure Lowering Treatment Trialists’ Collaboration: Effects of different blood-pressure-lowering regimens on major cardiovascular events: Results of prospectively-designed overviews of randomised trials. Lancet362 :1527 –1535,2003[CrossRef][Medline]
  4. Wannamethee SG, Shaper AG, Perry IJ: Serum creatinine concentration and risk of cardiovascular disease: A possible marker for increased risk of stroke. Stroke28 :557 –563,1997[Abstract/Free Full Text]
  5. Ninomiya T, Kiyohara Y, Kubo M, Tanizaki Y, Doi Y, Okubo K, Wakugawa Y, Hata J, Oishi Y, Shikata K, Yonemoto K, Hirakata H, Iida M: Chronic kidney disease and cardiovascular disease in a general Japanese population: The Hisayama Study. Kidney Int68 :228 –236,2005[CrossRef][Medline]
  6. Ruigrok YM, Buskens E, Rinkel GJ: Attributable risk of common and rare determinants of subarachnoid hemorrhage. Stroke32 :1173 –1175,2001[Abstract/Free Full Text]
  7. Abramson JL, Jurkovitz CT, Vaccarino V, Weintraub WS, McClellan W: Chronic kidney disease, anemia, and incident stroke in a middle-aged, community-based population: The ARIC study. Kidney Int64 :610 –615,2003[CrossRef][Medline]
  8. Koren-Morag N, Goldbourt U, Tanne D: Renal dysfunction and risk of ischemic stroke or TIA in patients with cardiovascular disease. Neurology67 :224 –228,2006[Abstract/Free Full Text]
  9. Rinkel GJ: Intracranial aneurysm screening: Indications and advice for practice. Lancet Neurol4 :122 –128,2005[CrossRef][Medline]
  10. Tonelli M, Moye L, Sacks FM, Kiberd B, Curhan G, for the Cholesterol and Recurrent Events (CARE) Trial Investigators: Pravastatin for secondary prevention of cardiovascular events in persons with mild chronic renal insufficiency. Ann Intern Med138 :98 –104,2003[Abstract/Free Full Text]
  11. Baigent C, Landry M: Study of Heart and Renal Protection (SHARP). Kidney Int Suppl84 :S207 –S210,2003[Medline]
  12. Procrit prescribing information. Amgen Inc., Thousand Oaks, California, and Ortho Biotech Products, Raritan, New Jersey, March2007
  13. KDOQI, National Kidney Foundation: KDOQI clinical practice guidelines and clinical practice recommendations for anemia in chronic kidney disease. Am J Kidney Dis47[Suppl 3] :S11 –S145,2006
  14. Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M, Reddan D, for the CHOIR investigators: Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med355 :2085 –2098,2006[Abstract/Free Full Text]
  15. Remuzzi G, Ingelfinger JR: Correction of anemia: Payoffs and problems. N Engl J Med355 :2144 –2146,2006[Free Full Text]
  16. Chrysant SG: Possible pathophysiologic mechanisms supporting the superior stroke protection of angiotensin receptor blockers compared to angiotensin-converting enzyme inhibitors: Clinical and experimental evidence. J Hum Hypertens19 :923 –931,2005[CrossRef][Medline]
  17. Julius S, Kjeldsen SE, Weber M, Brunner HR, Ekman S, Hansson L, Hua T, Laragh J, McInnes GT, Mitchell L, Plat F, Schork A, Smith B, Zanchetti A, for the VALUE trial group: Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: The VALUE randomised trial. Lancet363 :2022 –2031,2004[CrossRef][Medline]
  18. Rahman M, Pressel S, Davis BR, Nwachuku C, Wright JT, Whelton PK, Barzilay J, Batuman V, Eckfeldt JH, Farber MA, Franklin S, Henriquez M, Kopyt N, Louis GT, Saklayen M, Stanford C, Walworth C, Ward H, Wiegmann T, for the ALLHAT Collaborative Research Group: Cardiovascular outcomes in high-risk hypertensive patients stratified by baseline glomerular filtration rate. Ann Intern Med144 :172 –180,2006[Abstract/Free Full Text]
  19. Hansson L, Lindholm LH, Niskanen L, Lanke J, Hedner T, Niklason A, Luomanmäki K, Dahlöf B, de Faire U, Mörlin C, Karlberg BE, Wester PO, Björck JE: Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: The Captopril Prevention Project (CAPPP) randomised trial. Lancet353 :611 –616,1999[CrossRef][Medline]
  20. Wing LM, Reid CM, Ryan P, Beilin LJ, Brown MA, Jennings GL, Johnston CI, McNeil JJ, Macdonald GJ, Marley JE, Morgan TO, West MJ, for the 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 Med348 :583 –592,2003[Abstract/Free Full Text]
  21. Heart Outcomes Prevention Evaluation Study Investigators: Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med342 :145 –153,2000[Abstract/Free Full Text]
  22. Dahlöf B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U, Fyhrquist F, Ibsen H, Kristiansson K, Lederballe-Pedersen O, Lindholm LH, Nieminen MS, Omvik P, Oparil S, Wedel H, for the LIFE Study Group: Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): A randomised trial against atenolol. Lancet359 :995 –1003,2002[CrossRef][Medline]
  23. Lithell H, Hansson L, Skoog I, Elmfeldt D, Hofman A, Olofsson B, Trenkwalder P, Zanchetti A, for the SCOPE Study Group: The Study on Cognition and Prognosis in the Elderly (SCOPE): Principal results of a randomized double-blind intervention trial. J Hypertens21 :875 –886,2003[CrossRef][Medline]
  24. Weber MA, Julius S, Kjeldsen SE, Brunner HR, Ekman S, Hansson L, Hua T, Laragh JH, McInnes GT, Mitchell L, Plat F, Schork MA, Smith B, Zanchetti A: Blood pressure dependent and independent effects of antihypertensive treatment on clinical events in the VALUE Trial. Lancet363 :2049 –2051,2004[CrossRef][Medline]
  25. Høieggen A, Alderman MH, Kjeldsen SE, Julius S, Devereux RB, De Faire U, Fyhrquist F, Ibsen H, Kristianson K, Lederballe-Pedersen O, Lindholm LH, Nieminen MS, Omvik P, Oparil S, Wedel H, Chen C, Dahlöf B, for the LIFE Study Group: The impact of serum uric acid on cardiovascular outcomes in the LIFE study. Kidney Int65 :1041 –1049,2004[CrossRef][Medline]
  26. Jeerakathil T, Johnson JA, Simpson SH, Majumdar SR: Short-term risk for stroke is doubled in persons with newly treated type 2 diabetes compared with persons without diabetes: A population-based cohort study. Stroke38 :1739 –1743,2007[Abstract/Free Full Text]
  27. Adams HP, Adams RJ, Brott T, del Zoppo GJ, Furlan A, Goldstein LB, Grubb RL, Higashida R, Kidwell C, Kwiatkowski TG, Marler JR, Hademenos GJ, for the Stroke Council of the American Stroke Association: Guidelines for the early management of patients with ischemic stroke: A scientific statement from the Stroke Council of the American Stroke Association. Stroke34 :1056 –1083,2003[Free Full Text]
  28. Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7). National High Blood Pressure Education Program, Bethesda, National Heart, Lung, and Blood Institute, National Institutes of Health, August2004 . NIH Publication No. 04-5230
  29. Chalmers J, Turnbull F: Blood pressure lowering in patients with a previous stroke. In: Advanced Therapy in Hypertension and Vascular Disease, 1st Ed., edited by Mohler ER, Townsend R, Hamilton, Ontario, Canada, B.C. Decker,2006 ,130 –135
  30. PROGRESS Collaborative Group: Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet358 :1033 –1041,2001[CrossRef][Medline]
  31. Schrader J, Luders S, Kulschewski A, Hammersen F, Plate K, Berger J, Zidek W, Dominiak P, Diener HC, for the MOSES Study Group: Morbidity and mortality after stroke, eprosartan compared with nitrendipine for secondary prevention: Principal results of a prospective randomized controlled study (MOSES). Stroke36 :1218 –1226,2005[Abstract/Free Full Text]
  32. Bjerre LM, LeLorier J: Expressing the magnitude of adverse effects in case-control studies: The number of patients needed to be treated for one additional patient to be harmed. BMJ320 :503 –506,2000[Free Full Text]
  33. Diener HC, Sacco R, Yusuf S, Steering Committee, for the PRoFESS Study Group: Rationale, design and baseline data of a randomized, double-blind, controlled trial comparing two antithrombotic regimens (a fixed-dose combination of extended-release dipyridamole plus ASA with clopidogrel) and telmisartan versus placebo in patients with strokes: The Prevention Regimen for Effectively Avoiding Second Strokes Trial (PRoFESS). Cerebrovasc Dis23 :368 –380,2007[Medline]
  34. Teo K, Yusuf S, Sleight P, Anderson C, Mookadam F, Ramos B, Hilbrich L, Pogue J, Schumacher H, for the ONTARGET/TRANSCEND Investigators: Rationale, design, and baseline characteristics of 2 large, simple, randomized trials evaluating telmisartan, ramipril, and their combination in high-risk patients: The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial/Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (ONTARGET/TRANSCEND) trials. Am Heart J148 :52 –61,2004[CrossRef][Medline]




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