Analysis of Recent Papers in Hypertension

Beta blockers have been considered appropriate first-line drugs in the treatment of hypertension. Of those clinically available, atenolol is one of the most widely used β blockers that has often been used as a reference drug in randomized controlled trials of hypertension. Prompted by the recent Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study that found that a losartan-based treatment program prevented cardiovascular events (primarily stroke) better than an atenolol-based regimen in patients with left ventricular hypertrophy, Swedish investigators conducted a systematic review on the effect of atenolol on cardiovascular morbidity and mortality in hypertensive individuals. Performing a meta-analysis through The Cochrane Library, MEDLINE, relevant textbooks, and personal communication with hypertension experts, nine randomized controlled trials involving atenolol as first-step therapy in hypertension were included; four compared the drug with placebo or no treatment, and five compared atenolol with other hypertensive agents (thiazide-type diuretics, angiotensin-converting enzyme inhibitors, angiotensin type II receptor antagonists, or calcium channel blockers). Despite better blood pressure (BP) reduction compared with placebo in the four studies that involved 6825 patients treated for a mean of 4.6 years, atenolol, 50–100 mg q.d., did not significantly reduce all-cause mortality (relative risk [RR], 1.01; 95% confidence interval [CI], 0.89–1.15), cardiovascular mortality (RR, 0.99; 95% CI, 0.83–1.18), or myocardial infarction (MI) (RR, 0.99; 95% CI, 0.83-1.19). The risk of stroke, however, tended to be marginally lower in the atenolol group (RR, 0.85; 95% CI, 0.72–1.01), mainly influenced by one of the studies that reduced BP 18/11 mm Hg more on atenolol than placebo. In the five studies that included 17,671 patients comparing atenolol with other antihypertensive agents for a mean of 4.6 years, atenolol showed no advantage for preventing MI (RR, 1.04; 95% CI, 0.89–1.20). Despite the fact that there were no differences in BP reduction between the treatment arms, atenolol was associated with higher all-cause mortality (RR, 1.13; 95% CI, 1.02–1.25), higher cardiovascular mortality (RR, 1.16; 95% CI, 1.00–1.34), and higher rates of stroke (RR, 1.30; 95% CI, 1.12–1.50). The results of this analysis suggest that atenolol is not suitable as initial therapy for hypertension or as a reference standard in clinical outcome trials in hypertension.—Carlberg B, Samuelsson O, Lindholm LH. Atenolol in hypertension: is it a wise choice? Lancet. 2004;364:1684–1689. Beta blockers are often considered as a class of agents in hypertension guidelines. This meta-analysis suggests this may not be appropriate. Atenolol was no better than placebo when given in a dose of 50–100 mg o.d. in this meta-analysis (except for a reduced risk of stroke where atenolol lowered BP much more than placebo). When it was compared with other antihypertensive agents (with no differences in BP reduction between the treatment arms), atenolol in a dose of 50–100 mg q.d. was associated with an increased risk for death, cardiovascular death, and stroke. Why, then, is atenolol often used in the treatment of hypertension? Proponents for its use often quote the United Kingdom Prospective Diabetes Study (UKPDS), where atenolol was as effective as captopril for reducing cardiovascular risk in type 2 diabetic patients. In UKPDS, however, atenolol was given b.i.d., whereas in the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) trial, where losartan was shown to be more effective than atenolol in hypertensive patients with left ventricular hypertrophy, atenolol was given q.d., as in this meta-analysis. Atenolol does not have a 24-hour duration of effect, which is necessary in patients with left ventricular hypertrophy to effectively inhibit the trophic myocardial effects of the sympathetic nervous system and renin-angiotensin system in these high-risk individuals. The long-term use of metoprolol, propranolol, and timolol in post-MI patients is well established, while the benefits of atenolol have only been studied acutely to prevent ventricular free-wall rupture within the first 24 hours of the event. And, in that study, atenolol was given parenterally. Despite any evidence for its long-term use, atenolol is often used post-MI in the belief that the benefits of β blockade post-MI extend to all agents in the class, i.e, are a class effect. In addition, although extended-release metoprolol and carvedilol improve outcome in individuals with heart failure and reduced ejection fraction, atenolol is often used in this clinical situation as well, despite its lack of evidence. In the current meta-analysis, atenolol was no more protective post-MI than placebo, had no more favorable effect on cardiovascular morbidity and mortality than placebo, and had less benefit than other agents used to treat hypertension. Atenolol continues to be the most widely used β blocker in the treatment of hypertension. This meta-analysis does not support the use of this medication as first-line antihypertensive therapy in clinical practice or as a control drug in clinical hypertension outcomes trials. Perhaps it is time for this practice to stop. Results from clinical trials have found that angiotensin-converting enzyme (ACE) inhibitor therapy is effective in reducing the risk of heart failure (HF), myocardial infarction (MI), and death from cardiovascular causes in patients with HF or left ventricular (LV) systolic dysfunction. In addition, ACE inhibitors have been shown to reduce atherosclerotic complications in patients with vascular disease regardless of LV function. This has prompted several consensus guidelines to recommend ACE inhibitor therapy in all patients with either coronary artery disease (CAD) or disease affecting other arterial vascular beds. The recent Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) trial in patients with stable CAD and normal LV function suggests that these guidelines may need to be reconsidered. PEACE was a double-blind, placebo-controlled, randomized study comparing the effects of the ACE inhibitor trandolapril to placebo on the combined rate of nonfatal MI, death from cardiovascular causes, or the need for revascularization procedures in patients with documented CAD. While the original planned primary end point was death from cardiovascular causes or nonfatal MI, the primary end point was changed part way through the trial largely in response to slow recruitment. Secondary end points included combinations of the following: death from cardiovascular causes, nonfatal MI, coronary revascularization procedures, unstable angina, new HF, stroke, peripheral vascular disease, and cardiac arrhythmia. Men and women at least 50 years of age with CAD (documented by a history of previous MI, previous revascularization including both coronary artery bypass graft or percutaneous coronary intervention, or ≥50% obstruction in luminal diameter of a native coronary artery on catheterization), and an ejection fraction (EF) >40% were included. Exclusion criteria included having a hospitalization for unstable angina within the previous 2 months, coronary artery revascularization within the previous 3 months, requiring surgery for valvular heart disease, a serum creatinine >2.0 mg/dL or a serum potassium >5.5 mmol/L, and requiring ACE inhibitor or angiotensin receptor blocker therapy. A total of 8290 patients were enrolled between November 1996 and June 2000 at 187 sites in Canada, Italy, Puerto Rico, and the United States. After a 2-week run-in period with open-label trandolapril, 2 mg q.d., patients were randomly assigned in a double-blind fashion to either trandolapril or matching placebo (plus other medications that they may have been taking). After 6 months, they were up-titrated to 4 mg q.d. of trandolapril or placebo and followed until December 31, 2003 for a median follow-up time of 4.8 years. Baseline characteristics were similar between the two treatment groups. The mean age was 64 years, 18% were women, mean BP was 133/78 mm Hg, mean EF 58%, and mean serum cholesterol 192 mg/dL. Approximately 17% were diabetic, 55% had a history of MI, and 72% had a history of coronary revascularization (coronary artery bypass grafting or percutaneous intervention). Subjects were aggressively being treated for atherosclerotic risk reduction with over 90% taking aspirin or other antiplatelet therapy, 70% were on lipid lowering medication, and 60% were receiving β-blocker therapy. Systolic BP decreased by 1.4 mm Hg in the placebo group and 4.4 mm Hg in the trandolapril group (p<0.001). Despite this difference in achieved BP, there was no difference in the rates of the primary end point (22.5% incidence with placebo; 21.9% incidence with trandolapril) with a hazard ratio of 0.96 for trandolapril (95% confidence interval, 0.88–1.06; p=0.43), or any of its components. No benefit in terms of the primary end point was found in any prespecified subgroup (by age, gender, MI, history of revascularization, diabetes, cholesterol-lowering medication, or EF). Censoring data for all subjects who received openlabel trandolapril did not have any notable effect on the primary end point. Estimated hazard ratios for all of the prespecified secondary end points were 0.95–0.98 and did not reach statistical significance. Post hoc analysis of non-prespecified end points did demonstrate a decrease in new-onset diabetes and in death or hospitalization for HF in the ACE inhibitor group. Patients with stable CAD and normal LV systolic function derive no benefit from ACE inhibitor (trandolapril) therapy. ACE inhibitor therapy might not be needed in low-risk patients with CAD who are currently receiving standard intensive therapy. ACE inhibitor therapy might not be needed in low-risk patients with CAD who are currently receiving standard intensive therapy.—PEACE Trial Investigators. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med. 2004;351:2058–2068. The lack of clinical benefit seen in the PEACE trial stands in sharp contrast to the results of other recent studies involving subjects with atherosclerotic vascular disease, including the Heart Outcomes Prevention Evaluation (HOPE) and the European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease (EUROPA). In HOPE, high-risk patients with atherosclerotic vascular disease or diabetes and one of five additional risk factors experienced a favorable reduction in cardiovascular death, nonfatal MI, or stroke with ramipril (plus other medications) compared with placebo (plus other medications). In EUROPA, patients with stable CAD noted a significant reduction in cardiovascular death, nonfatal MI, or cardiac arrest with perindopril when compared with placebo. Like PEACE, neither HOPE nor EUROPA included patients with significant LV dysfunction. Perhaps the differences among the three studies can be accounted for by the different properties of the specific ACE inhibitor used or the dosage of the particular ACE inhibitor studied. While there may be some differences within the ACE inhibitor class, this seems unlikely to account for different study results. All three ACE inhibitors are considered “tissue specific” and have more in common than others within the class. All are o.d. and the clinical doses studied in these three trials have been shown to improve outcome. Trandolapril has been shown in the Trandolapril Cardiac Evaluation [TRACE] Study to reduce cardiovascular events in patients with reduced EF post-MI at the same dosage used in PEACE, although 31% of those in PEACE remained on 2 mg of trandolapril, possibly exposing a large group of study participants to an inadequate dose of the ACE inhibitor for effective renin-aldosterone system blockade. Perhaps the different end points evaluated in each study accounts for the difference, although post hoc analysis of the PEACE results using the primary end points for HOPE and EUROPA failed to change the reported results. The more likely explanation to account for the differences in these trials is the different patient populations studied and their baseline differences in risk. Patients enrolled in PEACE were at lower cardiovascular risk. More patients in PEACE than in HOPE or EUROPA had undergone coronary revascularization (73% vs. 40% vs. 54%, respectively) and received lipid-lowering therapy (70% vs. 29% vs. 56%, respectively). Mean baseline BP was lower in PEACE (133/78 mm Hg) than both HOPE (139/79 mm Hg) and EUROPA (137/82 mm Hg). In addition, PEACE subjects, on entry, had average BP values that were similar to subjects in HOPE and EUROPA after the addition of an ACE inhibitor. Determination of LV EF was not required in the HOPE and EUROPA studies, whereas an EF >40% was required to participate in the PEACE study. This suggested that the patient population in the other studies might have had more severe systolic HF on entry allowing a benefit to be realized. Overall, the annualized all-cause mortality in the PEACE population was only 1.6%, a rate similar to an age- and gender-matched population in general. In fact, the event rate in the HOPE placebo group was nearly double that of the PEACE placebo group at 4 years. Finally, as the steering committee allowed open-label ACE inhibitor therapy to be used part way through PEACE in patients with diabetes and either overt proteinuria or hypertension and microalbuminuria, the chance for any differences between groups to be detected was further minimized. Based on these results, it seems reasonable to conclude that low-risk patients with stable CAD and preserved LV function who are receiving aggressive management of other risk factors do not gain additional benefit from the addition of ACE inhibitor therapy. Chronic ACE inhibitor therapy should continue to be considered in high-risk patients with underlying vascular disease, such as those with uncontrolled hyperlipidemia or other cardiovascular risk factors. These include patients with poorly controlled BP, diabetes, HF with reduced EF, or current smokers. Practitioners must still stratify individual risk before a favorable cost-effective use of ACE inhibitor therapy can be justified. Osteoporotic hip fractures are associated with substantial morbidity and mortality, occurring in up to 40% of women and 10% of men during their lifetime. A recent prospective, population-based cohort study in older hypertensive men and women found that the use of thiazide-type diuretic therapy protected against hip fractures. Other observational studies have suggested that β-blocker use also decreases the risk of fracture in postmenopausal women. No studies, however, have evaluated β-blocker use and the risk of fractures in both men and women or the combined use of β blocker and thiazide-type diuretic therapy on future fracture risk. A case-control analysis of the United Kingdom General Practice Research Database, a large computer database with more than 3 million people from across the United Kingdom was performed. Investigators analyzed records from 30,601 patients (age range, 30–79 years; 60% women) who sustained a new fracture diagnoses from 1993–1999 and compared them with 120,819 controls who did not sustain a fracture. Matched by age, gender, practice site, and years of being in the database, case patients were excluded from the analysis if they had a medical disorder known to substantially affect bone metabolism such as osteoporosis, osteomalacia, Paget's disease of the bone, or the use of bisphosphonates. Forty-two percent of the fractures were of the hand or wrist, with 15% in the foot. Fractures were evenly distributed across age categories, but occurred more often in women than men (60% vs. 40%). Patients were classified as current users of a particular drug if their last prescription for the study drug was recorded <60 days before their fracture diagnosis. Adjustments were made for smoking, body mass index, number of practice visits, individual doses of the β blocker or thiazide-type diuretic used, or the use of 14 other classes of medications, including calcium channel blockers. Current β blocker users had a 23% blocker users had a 0.77; 95% confidence interval [CI], 0.72–0.83), thiazide-type diuretic users had a 20% reduction in the risk of fracture (OR, 0.80; 95% CI, 0.74–0.86), and those using both drugs had a 29% reduction in the risk of fracture (OR, 0.71; 95% CI, 0.64–0.79). Many elderly patients with hypertension are at risk of developing osteoporosis. Based on this large population-based case-control study, β blocker use or thiazide-type diuretic use is associated with a reduced risk of fracture. While controlled trials are necessary to confirm these findings, it appears that combining a β blocker with a thiazide-type diuretic lowers the risk of fracture even more.—Schlienger RG, Kraenzlin ME, Jick SS, et al. Use of beta-blockers and risk of fractures. JAMA. 2004;292:1326–1332. Recent studies have found that sympathetic nerve fibers exist in bone tissue with functional adrenergic receptors present in osteoblasts, as well as osteoclasts; i.e., the sympathetic nervous system appears to actively participate in the regulation of bone metabolism and remodeling. Animal studies in rats have found that β-adrenergic receptor blockade inhibits the sympathetic nervous systems's catabolic effect on bone, reducing both osteoclast number and function. While this has resulted in an increase in bone mass in animal studies, no investigations in humans have been done to address this issue. The present study is the first to evaluate the association of β-blocker use and risk of fracture in both men and women, as well as the combined effect of using β-blocker and thiazide-type diuretics together. The present study found that use of β-blocker therapy was associated with a reduced risk of fracture and that risk was further reduced with the addition of a thiazide-type diuretic. There are, however, a number of limitations to the current study. Since it was purely observational, it is impossible to prove cause and effect because it was a population-based cohort study based on voluntary participation; selection bias may have occurred in the population studied. Until future, prospective, randomized studies are completed, additional strategies including a diet rich in calcium and vitamin D, should be recommended in individuals at risk of skeletal fracture. At present, the findings of this large population-based case-control study suggest that the use of β blockers, either alone or in combination with thiazide diuretics, which increase urinary calcium absorption and decrease its excretion, help prevent fractures in men and women. This benefit further supports the use of these agents in the treatment of hypertension, particularly in patients at risk of developing osteoporosis.

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