Methodological and statistical reasons may explain why the U.K. Prospective Diabetes Study (UKPDS) was considered an outlier when compared with the other reviewed studies. Study design, report, and conduct weaknesses limit the conclusions of the UKPDS (1). Several of these weaknesses have been discussed in published articles(2,3). These weaknesses are as follows: 1) the UKPDS hypertension study was not blind, but open label; 2) the dosing regimens for captopril may not have been adequate (captopril was given twice per day; for the treatment of hypertension captopril should be given three times per day[4]); 3) the trial was not powered to detect differences in drug effects on cardiovascular events; 4) none of the blood pressure goals in the tight blood pressure control group (150/85 mmHg) or in the less tight blood pressure control group(initially 200/105 mmHg and recently 180/105 mmHg) are currently recommended according to U.S. or U.K. guidelines for the treatment of hypertension in patients with or without diabetes(5,6); 5) in the less tight blood pressure control group the first-line agent was furosemide, a diuretic not recommended for treatment of hypertension, according to the current guidelines(5,6);and 6) patients randomized to atenolol were significantly more likely to dropout of the trial than those randomized to captopril (35 vs. 22%, P < 0.0001), which may have created biased results.

These weaknesses may have obscured potentially important differences between captopril and atenolol and limited the possible generalizations of the potential benefits of more intense blood pressure control. The current recommended blood pressure target of <130/85 mmHg in patients with diabetes relies solely on observational data(5,7),not on definitive evidence from randomized controlled trials. It is not known whether a blood pressure target of <130/85 mmHg can be achieved safely in the majority of diabetic patients with hypertension. It remains to be established whether the more favorable outcomes in the tight blood pressure control group of the UKPDS are explained by better blood pressure control, the type of first-line drug being used (furosemide versus captopril or atenolol),chance, or any combination of these factors.

As described in previous reports, the Appropriate Blood Pressure Control in Diabetes (ABCD) study was conducted double-blind(8), whereas the Captopril Prevention Project (CAPPP) (9),the Fosinopril Versus Amlodipine Cardiovascular Events Randomized Trial(FACET) (10), and the UKPDS(1) were all conducted open label. None of the individual trials were adequately powered to assess effects on the risk of major cardiovascular events in diabetic patients with hypertension. The updated number of events in the nisoldipine and enalapril groups of ABCD were 27 and 9 for acute myocardial infarction (MI), 11 and 7 for stroke, 8 and 10 for heart failure, and 18 and 14 for all-cause mortality(M.P., personal communication with Dr. R. Estacio). We have estimated the number of combined cardiovascular events (47 in the nisoldipine and 29 in the enalapril group) by adding the number of new MI events and heart failure events to the previously reported number of combined events. In an analyses of the four trials combined with these new data, the odds ratio for ACE inhibitors versus other treatments (95% CI) was 0.72 (0.54-0.96) for acute MI,0.87 (0.59-1.27) for stroke, 0.81 (0.64-1.01) for cardiovascular events, and 0.90 (0.68-1.20) for all-cause mortality. The tests for heterogeneity were significant for the outcomes of acute MI and cardiovascular events when the data from the UKPDS were combined with the data from the other three trials(P < 0.001 for both outcomes), but the outcomes were not significant when the UKPDS was excluded from the meta-analysis, suggesting that the results of the UKPDS were different from the results of the other three trials. It cannot be assessed whether such heterogeneity was due to the many weaknesses of the UKPDS, the therapeutic equivalence of captopril and atenolol, or chance. Whether atenolol is equivalent to captopril for the treatment of diabetic patients with hypertension remains a question.

Furthermore, it was appropriate not to combine the UKPDS data with the data of the other trials because of the substantial heterogeneity generated by the inclusion of the UKPDS. Thus, only the data from the ABCD study, the CAPPP,and the FACET were included in the final meta-analytic calculations. When the data from the ABCD study, the CAPPP, and the FACET were combined, the patients randomized to an ACE inhibitor had a significantly lower risk of acute MI,cardiovascular events, and all-cause mortality than those randomized to an alternative treatment (Table 1). There were no such differences for the outcome of stroke. The revised data from the ABCD study did not change the conclusions of our meta-analysis(11).

Several recent comparative trials in hypertension have shown important differences in cardiovascular outcomes according to the type of drug administered, despite the minimal differences in blood pressure lowering. In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, doxazosin was inferior to chlorthalidone(12). In a meta-analysis of nine trials with ∼120,000 person-years of follow-up, calcium channel blockers were inferior to other drugs(13). In the present meta-analysis, ACE inhibitors appear to provide a special advantage in addition to blood pressure control when compared with the alternative agents tested. These data suggest that other mechanisms, possibly including the modulation of fibrinolysis, may be important in determining the therapeutic effects of antihypertensive drugs. Recently, the Fosinopril versus Amlodipine Comparative Treatments Study, a double-blind randomized controlled trial of 96 diabetic patients with hypertension, has shown that fosinopril resulted in a significantly (20%) lower level of plasminogen activator inhibitor 1 compared with amlodipine over 4 weeks of treatment(14). In brief, the available evidence suggests that the manner in which blood pressure is lowered is important. The advantages of more intense blood-pressure lowering here yet to be demonstrated in randomized controlled trials. While the present meta-analysis should not be considered conclusive, it seems beneficial to prefer an ACE inhibitor as a first-line agent when treating hypertension in diabetic patients.

M.P. serves on an advisory panel for Bristol-Myers Squibb (BMS); has accepted honoraria from BMS; and has received grants from BMS, Merck, Pfizer,and Parke-Davis. C.D.F. has received lecturing fees from Merck and King Pharmaceutical.

B.M.P. is on the events committee for the HERS Trial (Wyeth Ayerst) and received the Merck/SER Clinical Epidemiology Fellowship.

Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39.
McCormack J, Greenhalgh T: Seeing what you want to see in randomized controlled trials: versions and perversions of UKPDS data: United Kingdom Prospective Diabetes Study.
Nathan DM: Some answers, more controversy, from UKPDS: United Kingdom Prospective Diabetes Study.
Physician's Desk Reference
. Montvale, NJ,Medical Economics Company,
1997 Joint National Committee: The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.
Arch Intern Med
Ramsay LE, Williams B, Johnston GD, MacGregor GA, Poston L, Potter JF, Poulter NR, Russell G: British Hypertension Society guidelines for hypertension management 1999: summary.
Hansson L, Zanchetti A, Carruthers SG, Dahlof B, Elmfeldt D, Julius S, Menard 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) randomized trial: HOT Study Group.
Estacio RO, Jeffers BW, Hiatt WR, Biggi SL, Gifford N, Schrier RW:The effect of nisoldipine as compared with enalapril on cardiovascular events in patients with non-insulin-dependent diabetes and hypertension.
N Engl J Med
Hansson L, Lindholm LH, Niskanen L, Lanke J, Hedner T, Niklason A,Luomanmaki K, Dahlof B, de Faire U, Morlin C, Karlberg BE, Wester PO, Bjorck JE: Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomized trial.
Tatti P, Pahor M, Byington RP, DiMauro P, Guarisco R, Strollo G,Strollo F: Outcome results of the Fosinopril versus Amlodipine Cardiovascular Events randomized Trial in patients with hypertension and NIDDM.
Diabetes Care
Pahor M, Psaty BM, Alderman MH, Applegate WB, Williamson JD,Furberg CD: Therapeutic benefits of ACE inhibitors and other antihypertensive drugs in patients with type 2 diabetes.
Diabetes Care
The ALLHAT Collaborative Research Group: Major cardiovascular events in hypertensive patients randomized to doxazosin versus chlorthalidone in Antihypertensive and Lipid Lowering treatment to prevent Heart Attack Trial(ALLHAT): preliminary results.
Pahor M, Psaty BM, Alderman MH, Applegate WB, Williamson JD,Cavazzini C, Furberg CD: The health outcomes associated ith calcium antagonists compared with other first-line antihypertensive therapies: a meta-analysis of randomized controlled trials.
. In press
Pahor M, Franse LV, Deitcher SR, Cushman WC, Johnson KC, Shorr RI,Marchant K, Somes GW: The Fosinopril Versus Amlodipine Comparative Treatments Study (FACTS), a randomized trial to assess drug effects on PAI-1 (Abstract).
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