Stevo Julius

To determine whether blood pressure (BP) control in hypertensive patients achieved with combination drug therapy provides the same cardiovascular benefits as with single-agent therapy. Drug combinations, most often including hydrochlorothiazide (HCTZ), are now recommended for routine BP management, but their effects on cardiovascular event rates have not been compared with effective monotherapy. We conducted retrospective analyses of the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) data. VALUE compared cardiovascular event rates of valsartan and amlodipine. Patients with BPs not controlled (<140/90 mmHg) by the single agents had HCTZ and, if required, additional drugs of different classes, added. Using data pooled from the two treatment arms, we have now divided patients into those controlled on monotherapy and those controlled or not controlled by combination therapy. The primary study endpoint was first occurrence of cardiovascular death or nonfatal myocardial infarction or stroke. Comparisons between groups were by Cox regression, adjusted for on-treatment BP, age, prior cardiovascular events and left ventricular hypertrophy; the comparison between the monotherapy and combination therapy controlled groups was based on events occurring after 3 months by when the decision to use monotherapy or combination therapy was made. The primary endpoint occurred in 505 of 5924 (8.5%) monotherapy and 511 of 4621 (11.1%) combination therapy controlled patients: hazard ratio was 0.80 [95% confidence interval (CI) 0.70-0.90]. If these two groups were matched for baseline BPs and all events included from study baseline, the hazard ratio was 0.76 (95% CI 0.67-0.86). The difference between combination controlled and uncontrolled [434 of 3390 (12.8%)] groups was not significant [hazard ratio 0.90 (95% CI 0.80-1.03], nor when they were matched for baseline BPs [hazard ratio 0.95 (95% CI 0.81-1.11)]. Independent of prior cardiovascular history or baseline BP, hypertensive patients requiring combination therapy, which includes a thiazide diuretic for BP control, have a poorer cardiovascular prognosis than those controlled by monotherapy and only a nonsignificantly lower event rate than noncontrolled patients.

Most current guidelines recommend tighter blood pressure (BP) control in hypertensive patients with comorbidities. These recommendations are based on epidemiologic data indicating that cardiovascular risk increases at lower BP levels in hypertensive patients with comorbidities than in those without comorbidities. Hypertension guidelines usually reflect outcomes from previous studies, but current recommendations for patients with comorbidities have preceded the evidence. We review recent studies investigating whether these new targets can be achieved, whether they are well tolerated, and whether they positively affect the outcomes. The results of the few current studies about outcomes in lower BP target groups are either negative or somewhat—but not decidedly—positive. There is a need for new trials designed to evaluate the validity of current recommendations for tighter BP control in hypertensive patients with comorbidities. Additionally, existing data from published trials could be reanalyzed to provide further clarification.

In the Trial of Preventing Hypertension (TROPHY), volunteers with “high normal blood pressure” were randomized to 4 years of placebo (n = 381) or 2 years of 16 mg/d of candesartan (n = 391) followed by 2 years of placebo. At 2 years, there was a 26.8% absolute and a 66.3% relative risk reduction (P < 0.0001) of hypertension in the candesartan group. At study end, the former candesartan group had a 9.8% absolute and a 15.6% relative risk reduction (P < 0.007) of hypertension. The treatment was well tolerated. The Seventh Joint National Committee (JNC 7) changed the nomenclature from “high normal blood pressure” to “prehypertension” and widened the range to 120 to 139 and/or 80 to 89 mm Hg. Our results support the term “prehypertension” only for the 130 to 139 and/or 85 to 89 mm Hg group; in 4 years two thirds of the placebo group developed hypertension. We suggest stratifying the JNC classification into “prehypertension” (130–139 and/or 85–89 mm Hg) and “high normal blood pressure” (120–129 and/or 80–84 mm Hg). By the present JNC definition, only one quarter of adult men have normal blood pressure. Removing the disease label from another 28% would appropriately focus attention on high-risk prehypertension.

We are responding to two editorials^1,2 about the Trial of Preventing Hypertension (TROPHY) trial in the November 2006 issue of the American Journal of Hypertension. We wish to thank Drs. Meltzer, Persell, and Baker for their attention to TROPHY. Their editorials might motivate AJH readers to peruse the original TROPHY articles.^3,4 TROPHY is a unique, innovative study and the thought that new readers will be informed gives us a great deal of pleasure.

In the main Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) report, we investigated outcomes in 15 245 high-risk hypertensive subjects treated with valsartan- or amlodipine-based regimens. In this report, we analyzed outcomes in 7080 patients (46.4%) who, at the end of the initial drug adjustment period (6 months), remained on monotherapy. Baseline characteristics were similar in the valsartan (N=3263) and amlodipine (N=3817) groups. Time on monotherapy was 3.2 years (78% of treatment exposure time). The average in-trial blood pressure was similar in both groups. Event rates in the monotherapy group were 16% to 39% lower than in the main VALUE trial. In the first analysis, we censored patients when they discontinued monotherapy (“censored”); in the second, we counted events regardless of subsequent therapy (intention-to-treat principle). We also assessed the impact of duration of monotherapy on outcomes. No difference was found in primary composite cardiac end points, strokes, myocardial infarctions, and all-cause deaths with both analyses. Heart failure in the valsartan group was lower both in the censored and intention-to-treat analyses (hazard ratios: 0.63, P =0.004 and 0.78, P =0.045, respectively). Longer duration of monotherapy amplified between-group differences in heart failure. New-onset diabetes was lower in the valsartan group with both analyses (odds ratios: 0.78, P =0.012 and 0.82, P =0.034). Thus, despite lower absolute event rates in monotherapy patients, the relative risks of heart failure and new-onset diabetes favored valsartan. Moreover, these findings support the feasibility of comparative prospective trials in lower-risk hypertensive patients.