News From Recent Clinical Trials: Implications for Clinical Practice and the Treatment of Hypertension

In the control of elevated blood pressure (BP) in patients with diabetes, it is generally well documented that tight vs less-tight control gives major protection against microvascular and macrovascular disease. Nevertheless, a recent report from the United Kingdom Prospective Diabetic Study (UKPDS) confirmed the importance of continued long-term tight control.1 There was no legacy effect at 10-year follow-up vs the previously described benefit of tight vs less-tight control in the original study, and the statistically significant benefits of any diabetes-related end point and microvascular disease were lost. Moreover, between-group systolic BP differences were no longer apparent after 1 year. In the future, clinicians must remain vigilant in controlling BP in persons with type 2 diabetes (T2DM) and avoid therapeutic inertia or a laissez-faire attitude, even if BP is initially under good control. A recent report from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Vanguard phase trial demonstrated that with intensive pharmacotherapy, a mean systolic BP goal of 120 mm Hg can be achieved.2 The ACCORD Vanguard study had 491 participants with a mean age of 63 years: 52% were women, 30% were African American, and 11% were Hispanic. The mean duration of T2DM in these patients was 10 years and 32% had cardiovascular disease (CVD). By achieving a BP of 120/65 mm Hg in the intensive group vs 133/71 mm Hg in the standard group, the ACCORD trial demonstrated that with appropriate therapy, more aggressive BP targets are achievable. In the near future, researchers may report final results to resolve whether there is cardiovascular benefit from intensive BP reduction to a lower goal in patients with T2DM and hypertension. Increasingly, BP must be effectively treated outside the practices of subspecialists such as cardiologists, nephrologists, and endocrinologists. A wide range of clinicians, including primary care physicians, nurse practitioners, and physicians’ assistants, are needed to effectively curtail CVD and renal failure, especially in patients with T2DM and hypertension. A recent study from Canada demonstrated the benefit of a simplified approach to the treatment of uncomplicated hypertension.3 Although only approximately 15% of patients had a previous diagnosis of diabetes, this study, known as Simplified Treatment Intervention to Control Hypertension (STITCH), indicated that an algorithm using initial low- and fixed-dose combination therapy was beneficial when compared with guideline-based practice for the management of hypertension. The STITCH-care algorithm started with initial therapy with a low-dose angiotensin-converting enzyme (ACE) inhibitor/diuretic or angiotensin receptor blocker (ARB)/diuretic combination and successively mandated up-titration of the combination therapy to the highest dose and the initial therapy with an added calcium channel blocker (CCB) if needed. After 6 months, there was significantly more effective lowering of both systolic and diastolic BP in the STITCH-care vs guideline-care cohorts (−22.6±4.9 vs −17.5±5.2 mm Hg, respectively) (confidence interval [CI], 2.0–8.5 [P=.002]). STITCH-care practices demonstrated that 12.1% more patients were likely to reach their target BP at the end of 6 months (64.7% with STITCH-care vs 52.7% with guideline-care) (95% CI, 1.5%–22.4% [P=.026]). The STITCH authors concluded that, “Use of a simplified algorithm for the treatment of hypertension featuring the initial use of low-dose, fixed-drug combination drugs is implementable, accepted by family physicians, and results in improved blood pressure control.” Although performed in a nondiabetic cohort, a recent major trial (Studio Italiano Sugli Effetti Cardiovascolari del Controllo della Pressione Arteriosa Sistolica, or Italian Study on the Cardiovascular Effects of Systolic Blood Pressure Control [Cardio-Sis]) demonstrated the benefit of usual vs tight control of systolic BP.4 This is a major trial constructed to answer the question of whether optimal control of systolic BP vs usual control would be beneficial. A randomized open-label study was completed at 44 centers in Italy of 1111 nondiabetic patients with systolic BP ≥150 mm Hg. There were two treatment groups: usual control (target systolic BP <140 mm Hg [n=553]) and tight control (target systolic BP <130 mm Hg [n=558]). The primary end point of changes in electrocardiographic left ventricular hypertrophy was found in 11.4% in the usual-control patients (n=553) vs 17.0% in the tight-control group (n=557), with a hazard ratio of 0.63 (95% CI, 0.43–0.91; P=.013). An important secondary end point was death from any cause, including myocardial infarction, stroke, transient ischemic attack, and atrial fibrillation or admission for heart failure, angina, and/or coronary revascularization. This important secondary end point was seen in 4.8% of tight-control patients vs 9.4% of the usual-control patients with a hazard ratio of 0.50 (95% CI, 0.31–0.79; P=.003). Cardio-Sis results suggest that patients indeed do benefit from tighter BP control, although, as previously noted, the ACCORD study may confirm whether this benefit extends to patients with T2DM. In the future, clinicians will recognize that BP control itself is indeed the most important target for uncomplicated patients versus which medication is chosen for initial therapy. A recent meta-analysis of 147 randomized trials was constructed to determine the quantitative efficacy of different classes of antihypertensive medicines in preventing coronary heart disease and stroke.5 Overall, the study consisted of 464,000 patients who were known to have no history of vascular disease, coronary heart disease (CHD), or previous stroke. In the final analysis, Law and colleagues considered all the major classes of drugs similar within a few percentage points in comparing CHD events and cerebrovascular accidents. The only exceptions were the greater preventive effect of CCBs on cerebrovascular accidents with a risk reduction (RR) of 0.92 (95% CI, 0.85–0.98) and the greater protective effect of β blockers in patients with CHD with a RR of 29% (95% CI, 22%–34%). The authors concluded that to eliminate the deleterious effects of uncontrolled hypertension, it is more important to treat a wider range of patients effectively than to put undue attention on the particular drug used. The treatment of hypertension can best be approached by prevention. Physical inactivity and obesity are the hallmarks of the increasing prevalence of hypertension and diabetes in westernized societies. Aerobic exercise may have a benefit in BP control and a recent study confirmed that exercise capacity is related to diminished all-cause mortality in prehypertensive men.6 Utilizing graded exercise tests in 4478 prehypertensive male veterans, the report demonstrated a strong inverse and graded association between exercise and all-cause mortality. The patients selected for exercise tests were free of CHD and followed for a mean of 9 years. For every one metabolic equivalent increase in exercise capacity, there was a reduction in all-cause mortality, with a RR of 15% (P<.001). In addition to recommending the benefit of exercise to their patients, in the future, clinicians may utilize vitamin D supplementation more extensively to reduce cardiovascular risk and hypertension. A recent report from the Nurses’ Health Study demonstrated that levels of plasma 25-hydroxy vitamin D [25(OH)D] were inversely proportionate to BP or hypertension among young women.7 In a prospective study, 1484 women aged 32 to 52 years who did not have hypertension were analyzed for an association between plasma levels 25(OH)D and the odds of incident hypertension. Women in the lowest compared with the highest quartile of plasma 25(OH)D had an adjusted odds ratio for incident hypertension of 1.66 (95% CI, 1.11–2.48; P for trend=.01). Compared with women with sufficient levels, those with vitamin D deficiency (<30 ng/mL; 65.7% of the study population) had a multivariable odds ratio of 1.47 (95% CI, 1.10–1.97). Plasma 25(OH)D levels are inversely and independently associated with the risk of developing hypertension. If this association is causal, then a substantial proportion of hypertension incidence among young women could be attributed to suboptimal 25(OH)D. Previously, the benefits of ARBs have not been as conclusively demonstrated as the benefits of ACE inhibitors in major outcome trials. Nevertheless, a recent study from Japan, the KYOTO Heart Study, confirmed the beneficial effects of valsartan on morbidity and mortality in patients with uncontrolled hypertension placing them at high risk.8 The KYOTO Heart Study (n=3031) compared valsartan with conventional therapy vs another group that used all antihypertensives as needed except ACE inhibitors and ARBs. Primary end points were a composite of stroke, transient ischemic attack, acute myocardial infarction, angina, new or worsening heart failure, aorta aneurysm dissection, lower limb arterial obstruction, emergency thrombosis, dialysis, and doubling creatinine levels. Overall, approximately 27% of the patients had diabetes, and serum creatinine levels were similar with 0.87 (35%) for the valsartan group and 0.84 (38%) for the non-ARB group. A significant number of the patients were female (43%) and the mean age was 66 years. In both groups, BPs were effectively lowered from baseline (157/88 mm Hg) to the end of the study (133/76 mm Hg); however, compared with the non-ARB arm, the valsartan add-on arm had fewer primary end points (83 vs 155; hazard ratio, 0.55; 95% CI, 0.42–0.72, P=.00001). Impressively, this indicated a RR of 45% with a number needed to treat of only 21. The main effect was to reduce stroke and angina pectoris. The Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET) demonstrated the potential for telmisartan, an ARB, to decrease cardiovascular morbidity in high-risk patients.9 Although this trial does not suggest that ARBs replace ACE inhibitors, a secondary analysis of outcomes similar to those utilized in the landmark Heart Outcomes Prevention Evaluation (HOPE) study were positive, including an outcome of combined cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.87; 95% CI, 0.76–1.00 [P=.048]). Accordingly, in October 2009, the Food and Drug Administration gave telmisartan wider approval for reduction of risk of heart attack or stroke in persons 55 or older who cannot take an ACE inhibitor. Nevertheless, the effect of telmisartan on renal outcomes was analyzed and reported in July 2009.10 A total of 5927 adults with known CVD or diabetes with end-organ damage but without macroalbuminuria or heart failure who were intolerant of ACE inhibitors were enrolled. Measurements included composite renal outcome of dialysis or doubling of serum creatinine, changes in estimated glomerular filtration rate, and changes in albuminuria. The results showed no important differences in the composite renal outcome for telmisartan (1.96% for telmisartan [n=58] vs 1.55% for placebo [n=46]; hazard ratio, 1.29; 95% CI, 0.87–1.89 [P=.20]. One positive finding was that albuminuria increased less with telmisartan vs placebo. These findings suggested that during the period of the trial, ARBs in patients without substantial renal failure or proteinuria do not appear to add substantial benefits, although patients with higher degrees of renal disease or examination of outcomes over a longer period may alter these findings. The control of elevated BP and hypertension in high-risk patients, including persons with the cardiometabolic syndrome and T2DM is one of the most significant interventions available to reduce CVD and renal disease. The prevention of elevated BP via a healthy diet and exercise is the best path to curtail the persistent morbidity and mortality related to hypertension. The renin-angiotensin-aldosterone system is a prime target for intervention, including ACE inhibitors and, especially in ACE inhibitor–intolerant patients, ARBs.

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