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(Hypertension. 2004;44:637.)
© 2004 American Heart Association, Inc.

Scientific Contributions

Clinical Outcomes in the Diabetes Cohort of the International Verapamil SR-Trandolapril Study

George L. Bakris; Efrain Gaxiola; Franz H. Messerli; Giuseppe Mancia; Serap Erdine; Rhonda Cooper-DeHoff; Carl J. Pepine for the INVEST Investigators

From the Rush University Medical Center (G.L.B.), Chicago, Ill; Instituto Cardiovascular de Guadalajara (E.G.), Guadalajara, Mexico; Ochsner Clinic (F.H.M.), New Orleans, La; Clinica Medica and Centro Interuniversitario di Fisiologia Clinica e Ipertensione (G.M.), Università degli Studi Milano-Bicocca, Milan, Italy; Cardiology Institute (S.E.), University of Istanbul, Istanbul, Turkey; and University of Florida (R.C-D., C.J.P.), Gainesville, Fla.

Correspondence to George Bakris, MD, Rush Medical University, 1700 W Van Buren St, Suite 470, Chicago, IL. E-mail George_Bakris{at}rush.edu

	Abstract

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The INternational VErapamil SR-Trandolapril study (INVEST) had 6400 of 22 576 (28.3%) participants with diabetes at entry. The objectives of this prespecified analysis were to compare antihypertensive treatment strategies in the diabetes cohort (verapamil SR-based [n=3169] versus atenolol-based [n=3231]) and identify predictors for the primary outcome (a composite of first occurrence of all-cause death, nonfatal myocardial infarction, or nonfatal stroke). During a mean follow-up of 2.7 years, 913 participants with diabetes experienced a primary outcome event, with no significant difference between treatment strategies (14.6%, verapamil SR versus 13.9%; atenolol hazard ratio, 1.05; 95% confidence interval, 0.92 to 1.19). Risk for the primary outcome increased with presence of baseline heart failure, renal impairment, US residency, age, previous stroke/transient ischemic attack, previous myocardial infarction, peripheral vascular disease, or smoking. High systolic and diastolic pressures during follow-up also were associated with increased risk, as were low diastolic pressures. Antihypertensive treatment with a verapamil SR or atenolol strategy resulted in similar rates of cardiovascular outcomes in coronary artery disease (CAD) patients with diabetes. Thus, a verapamil SR-based antihypertensive treatment strategy is an alternative to a ß-blocker–based strategy in adults with CAD and diabetes.

Key Words: blood pressure • diabetes mellitus • coronary artery disease • calcium antagonists

	Introduction

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Adults with diabetes are 2 to 4x more likely to die from heart disease and stroke than those without diabetes. This risk increases for adults with hypertension (HT) and diabetes.¹ To reduce cardiovascular risk in those with diabetes, more aggressive blood pressure (BP) control is needed compared with the general population. The sixth report of the Joint National Committee (JNC VI) recommended a target BP of <130/85 mm Hg for persons with diabetes, and the seventh report (JNC 7) recommends a target of <130/80 mm Hg.^2,3

Postmyocardial infarction studies demonstrate that ß-blockers and diuretics, alone or in combination, reduce cardiovascular mortality in coronary artery disease (CAD), with ß-blockers being preferred.^2,4 However, use of ß-blockers or diuretics is associated with metabolic abnormalities, including impaired glucose tolerance, insulin resistance and hypokalemia, and increased risk for new-onset diabetes.^5–9

Nondihydropyridine calcium antagonists (non-DHPCAs) such as verapamil SR are recommended as an alternative to ß-blockers for angina relief in persons with CAD-HT.^2,3 Verapamil SR effectively reduces BP¹⁰ and clinical outcomes in patients with CAD.¹¹ Moreover, non-DHPCAs are generally considered metabolically neutral.^7,10

Previous outcome studies evaluated the effect of BP reduction with different antihypertensive medications in a cohort of established CAD and HT but without concomitant use of renin-angiotensin system (RAS) blockers (ie, angiotensin-converting enzyme [ACE] inhibitors and angiotensin receptors blockers [ARBs]) and lower BP goals. The INternational VErapamil SR-Trandolapril study (INVEST) evaluated 2 recommended antihypertensive regimens in a CAD-HT population,² with the option of adding an ACE inhibitor or hydrochlorothiazide (HCTZ), to achieve JNC VI BP targets.¹² This prespecified analysis reports outcomes in the cohort with diabetes.

	Methods

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Study Design
INVEST was a prospective, randomized, open trial with blinded end point design comparing clinical outcomes in 22 576 participants with CAD-HT randomized to a verapamil SR-based or atenolol-based antihypertensive treatment strategy. Results from the main trial were reported previously.¹²

Of these participants, 6400 (28.3%) had diabetes at baseline (defined by a history of diabetes mellitus and/or use of oral hypoglycemic medication or insulin) and were followed for a mean duration of 2.7 years (Figure 1). The objectives of this prespecified cohort analysis were to compare risk for adverse outcomes between strategies and to identify predictors of risk.

View larger version (19K): [in this window] [in a new window]   Figure 1. Participant flow. ITT indicates intention to treat.

Treatment Algorithm
Participants were randomized to 240 mg per day of verapamil SR or 50 mg per day of atenolol and titrated to maximal doses to achieve JNC VI² target BP of <130/85 mm Hg.¹² If BP goal was not achieved, trandolapril (0.5 to 8 mg per day) and HCTZ (12.5 to 100 mg per day) were recommended as primary and secondary add-on agents in the verapamil SR strategy, and the sequence was reversed in the atenolol strategy. Trandolapril also was recommended for participants with diabetes, heart failure, or renal impairment.^2,13

Study Outcomes
The primary outcome was a composite of first occurrence of all-cause death, nonfatal myocardial infarction (MI), or nonfatal stroke.¹² Secondary outcomes included all-cause death, nonfatal MI and nonfatal stroke, BP control (<130/85 mm Hg), cardiovascular hospitalizations, and cardiovascular death.

Statistical Analysis
Outcomes were assessed with Cox proportional hazards models and Kaplan–Meier plots. Unless otherwise specified, a P value <0.05 was considered statistically significant. A stepwise Cox proportional hazards model identified baseline factors associated with the primary outcome. Five prespecified covariates (age, race/ethnicity [white, Asian, black, Hispanic, multiracial/other], gender, previous MI, and heart failure [class I–III]) and a factor for strategy were forced entries in the model. Additional covariates were selected if significant at the 10% level.

The association of follow-up BP with the primary outcome was explored with a Cox model that included factors for average systolic BP (SBP) and average SBP squared. Average SBP and diastolic BP (DBP) were derived from postbaseline BP measurements before primary outcome or censoring, or baseline SBP and DBP for participants without postbaseline measurements were used.

Data were captured and stored in Oracle database tables version 7.1. Statistical analyses were performed using SAS version 8.2 (SAS Institute).

	Results

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Baseline Characteristics
Baseline characteristics were comparable between strategies (Table 1), except that a higher proportion of women reported use of hormone replacement therapy in the atenolol strategy.

View this table: [in this window] [in a new window]   TABLE 1. Baseline Characteristics of Participants With Diabetes

Treatment Strategies
Table 2 details medication use at 24 months. The majority of participants required add-on therapy with differences in use of trandolapril and HCTZ by strategy. More than half the participants (59.3%) were taking aspirin or antiplatelet agents throughout the trial. This did not differ between groups, nor were there differences in antidiabetic medications. However, among those taking oral hypoglycemic agents at baseline, initiation of insulin treatment was greater in the atenolol group (5.2% verapamil SR versus 7.9% atenolol; P=0.01). Increases in insulin use were not related to sex, age, or body mass index (BMI).

View this table: [in this window] [in a new window]   TABLE 2. Strategy and Nonstrategy Drug Exposure of Participants with Diabetes at 24 Months

BP and Heart Rate
Similar reductions in BP were present in both strategies (Figure 2). Greatest BP reductions occurred within 6 months of randomization and were maintained to trial end. BP goal (<130/85 mm Hg) was achieved in >40% of all participants annually throughout the 4-year follow-up, with the highest prevalence at 2 years (44.0% and 43.9% for verapamil SR and atenolol strategies, respectively; P=0.94). Mean resting heart rate was 3.4 bpm less at 24 months in the atenolol group (P<0.001).

View larger version (14K): [in this window] [in a new window]   Figure 2. Mean SDPs and DBPs over 4 years by treatment strategy in the diabetes cohort.

Primary and Secondary Outcomes
The primary outcome occurred in 913 (14.3%) of diabetes participants; this compared with 1356 (8.4%) of participants without diabetes (hazard ratio [HR], 1.77; 95% confidence interval [CI], 1.63 to 1.93). Time to primary outcome demonstrated no difference between strategies (Figure 3). Risk for primary and secondary outcomes did not differ by strategy (Table 3). Presence of prior heart failure, US residency, increas-ing age, and previous MI significantly increased risk for the primary outcome in the diabetes cohort. In addition, presence of prior renal impairment (HR, 1.76; 95% CI, 1.39 to 2.25), previous stroke/transient ischemic attack (HR, 1.42; 95% CI, 1.19 to 1.71), peripheral vascular disease (HR, 1.34; 95% CI, 1.15 to 1.56), and smoking (HR, 1.23; 95% CI, 1.07 to 1.41) also significantly increased risk in the diabetes cohort.

View larger version (15K): [in this window] [in a new window]   Figure 3. Kaplan–Meier plot for time to composite primary outcome by treatment strategy in the diabetes cohort.

View this table: [in this window] [in a new window]   TABLE 3. Primary and Secondary Clinical Outcomes by Treatment Strategy (Unadjusted) in the Diabetes Cohort

BPs of 140/90 mm Hg were associated with reduced risk of the primary outcome, an effect that extends to a BP of 110/60 mm Hg (Figure 4). Risk appears to increase at levels <110/60 mm Hg, but this is limited by the very small sample size.

View larger version (31K): [in this window] [in a new window]   Figure 4. Incidence (percentage with 95% CI) and risk (HR) of primary outcome in the diabetes cohort by mean follow-up: A, SDPs; B, DBPs. CIs were cut off at 100%. Reference groups (HR=1) were 140 mm Hg and 90 mm Hg for systolic and diastolic pressures, respectively. Note the power of the HR for the <110/60 mm Hg group is severely limited because of a small sample size.

Finally, an on-treatment analysis of randomized drugs, using 50 mg per day of atenolol as a reference group, indicates a trend for reduced risk of the primary outcome with the addition of 2 mg per day of trandolapril to the verapamil SR–based strategy or 12.5 mg per day of HCTZ to atenolol-based strategy. Increasing doses of trandolapril or HCTZ to a maximum of 8 mg per day or 50 mg per day, respectively, did not change this benefit.

Adverse Events
Both strategies were well tolerated with no differences in adverse events, except for constipation (1.6% verapamil SR versus 0.2% atenolol; P=0.001) and wheezing (0.2% verapamil SR versus 0.4% atenolol; P=0.04).

	Discussion

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Although a large body of trial data supports the recommended use of ß-blockers to reduce mortality in adults with diabetes after MI or heart failure,^3,14 this is the first large outcome study in CAD participants to document a similar cardiovascular outcome benefit between ß-blocker–based and non-DHPCA–based strategies. Moreover, many of the ß-blocker trials in CAD occurred before use of RAS blockers, which have been shown to reduce mortality in persons with CAD and diabetes.¹⁵ The observed benefits of ß-blockers in earlier studies may have been less dramatic if RAS blockers were the comparator agent, or more dramatic if these different classes were used in combination. The data reported here are important additions to the spectrum of antihypertensive treatment data in the diabetes population, particularly because so many adults with diabetes develop CAD.

There are important similarities and differences between INVEST and recent antihypertensive trials that included cohorts with diabetes regardless of CAD.^5,16,17Although a diuretic was more effective than a dihydropyridine calcium antagonist or an ACE inhibitor for reducing risk of heart failure in the diabetes cohort of the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT),⁵ there were no differences between regimens in this cohort for the primary outcome. In the CAptopril Prevention Project (CAPPP), an ACE inhibitor was superior to a diuretic/ß-blocker combination in preventing cardiovascular events in hypertensive participants with diabetes.¹⁶ The Controlled Onset Verapamil INvestigation of Cardiovascular Endpoints (CONVINCE) trial used antihypertensive agents similar to INVEST. The primary outcome of the diabetes subgroup in the main report were similar between verapamil-based and ß-blocker–based treatments.¹⁷ Thus, BP lowering with agents other than ß-blockers reduced cardiovascular events in people with diabetes, many of whom had documented CAD.

INVEST is one of the few trials to document that almost half of the participants with diabetes achieved the JNC VI (<130/85 mm Hg) BP goal.² This control rate is much higher than that observed in the general diabetes population (25%),¹⁸ in the practice-based setting (22%),¹⁹ or in other trials.⁸ The results reported here, in addition to the primary results,¹² reinforce the effectiveness of non-DHPCAs and ß-blockers in controlling BP and demonstrate that although BP control is difficult to achieve in the patient with diabetes, it is attainable.

Participants with diabetes in INVEST had almost twice the risk for cardiovascular events compared with those without diabetes, similar to previous reports.^1,16,20 Hypercholesterolemia and higher BMI were not associated with increased risk of the primary outcome in this trial. However, >67% of patients reporting hypercholesterolemia at baseline also reported use of lipid-lowering agents, which likely affected risk; and studies suggest that waist circumference more accurately defines risk than BMI,^21,22 which was not assessed in INVEST.

Risk analyses in 2 trials in which BP levels were randomized supports the concept of lower BP levels for CAD patients with diabetes.^23,24 However, in small observational studies, an excessively low DBP was associated with increased cardiovascular risk in angina patients.²⁵ In INVEST, <1% (62 of 6400) of diabetes participants achieved a BP <110/60 mm Hg; of these, only 28% had a primary outcome. Given the small number of participants who achieved these pressures, no firm statements can be made for this subgroup. However, guidelines are clear about avoiding such BP levels in such a subgroup.

Results from the on-treatment analysis suggest that combination therapy is more effective for reducing adverse outcomes. These data complement previous studies that demonstrated improved outcomes for combination versus monotherapy²⁶ and provide novel information on the effectiveness of a non-DHPCA and ACE inhibitor used in combination. It is clear that combination therapy is needed to achieve BP goal in those with diabetes and CAD.³ Events related to stroke and, to a lesser extent, CAD, are related to BP level;^4,27 this would explain why a similar benefit in cardiovascular outcome was seen in both INVEST groups.

This subanalysis does have some limitations. Although this was a prespecified analysis, it represents a subgroup of participants from the overall study. Participants with diabetes were not specifically randomized but were part of a larger randomized population. Also, diabetes status was based on history of diabetes and/or use of antidiabetic agents at baseline and was not confirmed by laboratory testing; however, others have verified the accuracy of using self-reports.²⁸

We conclude that use of a verapamil SR–based strategy effectively achieves BP goal in adults with diabetes, HT, and CAD, similar to that of an atenolol-based strategy with no difference in cardiovascular mortality and morbidity outcomes.

Perspectives
It is clear that multiple BP-lowering agents are needed to achieve BP goals in the CAD population¹² and that achievement of such goals translates into reduced cardiovascular outcomes, especially in those with diabetes. Current guidelines of the American Diabetes Association state that any approved antihypertensive agent can be used, although ACE inhibitors, ARBs, ß-blockers, and diuretics are preferred agents.¹ Data from INVEST, together with other studies, support the use of a non-DHPCA combined with an ACE inhibitor as an alternative initial therapy to a ß-blocker–based strategy for patients with diabetes and CAD.

	Acknowledgments

 
INVEST was funded by grants from Abbott Laboratories and the University of Florida Research Foundation and Opportunity Fund. Investigators conceived the study and designed and conducted it independently of all sponsors. G.L.B. had full access to all data.

	Footnotes

 
The following conflicts of interest have been disclosed: G.B. has consultant agreements with and serves on speakers’ bureaus for AstraZenaca, Abbott Laboratories, Amersham, Alteon, Biovail, Boehringer Ingelheim, Bristol-Myers Squibb, Forest, GlaxoSmithKline, Merck, Novartis, Sanofi-Synthelabo, Sankyo, and Solvay and has received grant support from AstraZenaca, Abbott Laboratories, Amersham, Alteon, Boehringer Ingelheim, Forest, GlaxoSmithKline, Merck, Novartis, Sankyo, and Solvay. Dr Messerli has received honoraria from Merck, Pfizer, Abbott Laboratories, Forest, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Biovail, Solvay, Reliant, and Pharmacia. R.C.-D. has received grant support from Abbott Laboratories and Pfizer. C.J.P. has received grant support from Abbott Laboratories, AstraZeneca, Aventis Pharmaceuticals, Inc., Berlex Laboratories, Inc., Bristol-Myers Squibb, Sanofi Company, CV Therapeutics, Monarch Pharmaceuticals, Novartis, Pfizer, and Wyeth-Ayerst Laboratories and has been a consultant for Abbott Laboratories. C.J.P. and R.C.-D. are coinventors of the online prescribing system used in INVEST, which is licensed to the University of Florida.

Received June 19, 2004; first decision July 8, 2004; accepted August 24, 2004.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Standards of medical care in diabetes. Diabetes Care. 2004; 27 (suppl 1): S15–35.
2. Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. 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.[Abstract]
3. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003; 42: 1206–1252.[Abstract/Free Full Text]
4. Turnbull F. Effects of different blood pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet. 2003; 362: 1527–1535.[CrossRef][Medline] [Order article via Infotrieve]
5. ALLHAT Officers and Coordinators, ALLHAT Collaborative Research Group. 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). J Am Med Assoc. 2002; 288: 2981–2997.[Abstract/Free Full Text]
6. Lindholm LH, Persson M, Alaupovic P, Carlberg B, Svensson A, Samuelsson O. Metabolic outcome during 1 year in newly detected hypertensives: results of the Antihypertensive Treatment and Lipid Profile in a North of Sweden Efficacy Evaluation (ALPINE Study). J Hypertens. 2003; 21: 1563–1574.[CrossRef][Medline] [Order article via Infotrieve]
7. Chellingsworth MC, Kendall MJ, Wright AD, Singh BM, Pasi J. The effects of verapamil, diltiazem, nifedipine and propranolol on metabolic control in hypertensives with non-insulin dependent diabetes mellitus. J Hum Hypertens. 1989; 3: 35–39.[Medline] [Order article via Infotrieve]
8. Lindholm LH, Ibsen H, Dahlof B, Devereux RB, Beevers G, de Faire U, Fyhrquist F, Julius S, Kjeldsen SE, Kristiansson K, Lederballe-Pedersen O, Nieminen MS, Omvik P, Oparil S, Wedel H, Aurup P, Edelman J, Snapinn S. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention for Endpoint Reduction in Hypertension Study (LIFE): a randomized trial against atenolol. Lancet. 2002; 359: 1004–1010.[CrossRef][Medline] [Order article via Infotrieve]
9. Gress TW, Nieto FJ, Shahar E, Wofford MR, Brancati FL. Hypertension and antihypertensive therapy as risk factors for type 2 diabetes mellitus. Atherosclerosis Risk in Communities Study. N Engl J Med. 2000; 342: 905–912.[Abstract/Free Full Text]
10. Ding YA, Chou TC, Lin KC. Effects of long-acting propranolol and verapamil on blood pressure, platelet function, metabolic and rheological properties in hypertension. J Hum Hypertens. 1994; 8: 273–278.[Medline] [Order article via Infotrieve]
11. Hansen JF. Effect of verapamil on mortality and major events after acute myocardial infarction (the Danish Verapamil Infarction Trial II-DAVIT II). Am J Cardiol. 1990; 66: 779–785.[CrossRef][Medline] [Order article via Infotrieve]
12. Pepine CJ, Handberg EM, Cooper-DeHoff RM, Marks RG, Kowey P, Messerli FH, Mancia G, Cangiano JL, Garcia-Barreto D, Keltai M, Erdine S, Bristol HA, Kolb HR, Bakris GL, Cohen JD, Parmley WW. A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease: the International Verapamil-Trandolapril Study (INVEST): a randomized controlled trial. J Am Med Assoc. 2003; 290: 2805–2816.[Abstract/Free Full Text]
13. Estacio RO, Jeffers BW, Hiatt WR, Biggerstaff SL, Gifford N, Schrier RW. The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension. N Engl J Med. 1998; 338: 645–652.[Abstract/Free Full Text]
14. Haas SJ, Vos T, Gilbert RE, Krum H. Are beta-blockers as efficacious in patients with diabetes mellitus as in patients without diabetes mellitus who have chronic heart failure? A meta-analysis of large-scale clinical trials. Am Heart J. 2003; 146: 848–853.[CrossRef][Medline] [Order article via Infotrieve]
15. Fox KM. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA Study). Lancet. 2003; 362: 782–788.[CrossRef][Medline] [Order article via Infotrieve]
16. Niskanen L, Hedner T, Hansson L, Lanke J, Niklason A. Reduced cardiovascular morbidity and mortality in hypertensive diabetic patients on first-line therapy with an ACE inhibitor compared with a diuretic/beta-blocker-based treatment regimen: a subanalysis of the Captopril Prevention Project. Diabetes Care. 2001; 24: 2091–2096.[Abstract/Free Full Text]
17. Black HR, Elliott WJ, Grandits G, Grambsch P, Lucente T, White WB, Neaton JD, Grimm RH Jr, Hansson L, Lacourciere Y, Muller J, Sleight P, Weber MA, Williams G, Wittes J, Zanchetti A, Anders RJ. Principal results of the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) Trial. J Am Med Assoc. 2003; 289: 2073–2082.[Abstract/Free Full Text]
18. Hajjar I, Kotchen TA. Trends in prevalence, awareness, treatment, and control of hypertension in the United States, 1988–2000. J Am Med Assoc. 2003; 290: 199–206.[Abstract/Free Full Text]
19. Singer GM, Izhar M, Black HR. Guidelines for hypertension: are quality-assurance measures on target? Hypertension. 2004; 43: 198–202.[Abstract/Free Full Text]
20. Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care. 1993; 16: 434–444.[Abstract]
21. Janssen I, Katzmarzyk PT, Ross R. Waist circumference and not body mass index explains obesity-related health risk. Am J Clin Nutr. 2004; 79: 379–384.[Abstract/Free Full Text]
22. Lofgren I, Herron K, Zern T, West K, Patalay M, Shachter NS, Koo SI, Fernandez ML. Waist circumference is a better predictor than body mass index of coronary heart disease risk in overweight premenopausal women. J Nutr. 2004; 134: 1071–1076.[Abstract/Free Full Text]
23. 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: 703–713.[Abstract/Free Full Text]
24. Hansson L, Zanchetti I, Carruthers SG, Dahlof B, Elmfeldt D, Julius S, Menard J, Rahn KH, Wedel H, Westerling S; for the HOT Study Group. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet. 1998; 351: 1755–1762.[CrossRef][Medline] [Order article via Infotrieve]
25. Farnett L, Mulrow CD, Linn WD, Lucey CR, Tuley MR. The J-curve phenomenon and the treatment of hypertension. Is there a point beyond which pressure reduction is dangerous? J Am Med Assoc. 1991; 265: 489–495.[Abstract]
26. Tatti P, Pahor M, Byington RP, Di Mauro P, Guarisco R, Strollo G, Strollo F. Outcome results of the Fosinopril Versus Amlodipine Cardiovascular Events Randomized Trial (FACET) in patients with hypertension and NIDDM. Diabetes Care. 1998; 21: 597–603.[Abstract]
27. 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. Lancet. 2004; 363): 2049–2051.[CrossRef][Medline] [Order article via Infotrieve]
28. Kriegsman DM, Penninx BW, van Eijk JT, Boeke AJ, Deeg DJ. Self-reports and general practitioner information on the presence of chronic diseases in community dwelling elderly. A study on the accuracy of patients’ self-reports and on determinants of inaccuracy. J Clin Epidemiol. 1996; 49: 1407–1417.[CrossRef][Medline] [Order article via Infotrieve]

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