Peter M Nilsson
Department of Medicine
New studies in hypertension can increase our knowledge-base on how to evaluate and treat risk patients, as manifested in different guidelines on hypertension treatment that have been published in the past two years.(1–5)
These new studies must, however, be interpreted within the context of each country, with its clinical tradition, financial situation and patient categories. Newer drugs are often more expensive than conventional treatments, but they may sometimes offer extra clinical benefits or fewer adverse effects. Therefore, it is of great importance that new trials are planned and carried out to test whether this holds true for individual drugs belonging to new classes.
Presentation of the VALUE trial
The recently published Valsartan Antihypertensive Long-term Use Evaluation (VALUE) intervention study included 15,245 hypertension patients over the age of 50 years (42% women; 89% Caucasian) with high cardiovascular risk (46% with coronary disease; 33% with diabetes; and 24% smoking) from 31 countries. The VALUE trial compared the effects of valsartan, an angiotensin-II receptor blocker (ARB), with those of amlodipine, a dihydropyridine-type calcium antagonist.(6,7) The choice of amlodipine as the drug for comparison led to the trial not being approved in Sweden, where authorities asked for a comparative study between valsartan and conventional drug therapy (thiazide diuretics and/or beta-receptor blockers). However, amlodipine is currently a well-studied drug that, in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) study, has been found to have the same clinical effects on primary endpoint outcome as chlorothalidone, a thiazide diuretic, and lisinopril, an angiotensin-converting enzyme (ACE) inhibitor.(8)
The inclusion criteria in VALUE was a systolic blood pressure >160–210mmHg and/or a diastolic blood pressure >95–105mmHg, or previously known treatment of hypertension, often based on drug combination. The main hypothesis for the VALUE trial was that an ARB (valsartan) would be more beneficial than the comparative drug (amlodipine) at equal levels of blood pressure control. Thus, it was of great importance to achieve similar blood pressure control in both treatment arms, which was previously achieved in hypertension trials such as the Losartan Intervention For Endpoint reduction in hypertension study (LIFE)(9) and the second Australian National Blood Pressure study (ANBP2),(10) but not in other ones, such as the Captopril Prevention Project (CAPPP)(11) and ALLHAT.(8)
After a mean treatment period of 4.2 years, a poorer blood pressure control (4.0/2.1mmHg after one month; 1.5/1.3mmHg after one year) was found in patients randomised to valsartan (n=7,649; mean dosage 152mg) compared with patients randomised to amlodipine (n=7,696; mean dosage 8.5mg). These results were obtained despite add-on treatment in 40–50% of all patients, mostly by use of hydrochlorothiazide in increasing dosages (12.5–25mg). There was no difference in the primary composite endpoint between treatment arms. The primary endpoint occurred in 810 patients in the valsartan group (10.6%, 25.5 per 1,000 patient-years) and in 789 patients in the amlodipine group (10.4%, 24.7 per 1,000 patient-years; hazard ratio [HR] 1.04, 95% CI 0.94–1.15, p=0.49). On the other hand, the number of patients with newly detected type 2 diabetes was significantly lower in the valsartan arm (–23% relative risk reduction), with a HR of 0.77 (0.69–0.86). This might be of great importance in the longer perspective for the risk of encountering macro- and/or microvascular complications. The less effective blood pressure controls in the valsartan arm have probably contributed to the increase in the rate of myocardial infarction (HR 1.19 [1.02–1.38]), especially nonfatal, and stroke (HR 1.15 [0.98–1.35]) in patients on this treatment. However, the risk of congestive heart failure (CHF) was lower in the valsartan-treated patients than for patients treated with amlodipine (HR 0.89 [0.77–1.03]).
Some design problems in the VALUE trial need to be considered. For example, there was no “washout, run-in” period in VALUE (nor in ALLHAT),(8) and this may have implied “carry-over” effects from previous treatment, as only 8% of the patients in VALUE were previously untreated, drug-naive patients. In addition, and despite strong advice to treat vigorously from researchers monitoring the study, the same degree of blood pressure control was not achieved in all study participants. This could have been influenced by the starting dose of valsartan that was used. Theoretically, results could be different if the starting dose were higher than 80mg (the typical starting dose).
Following the VALUE trial, the investigators have also published a post-hoc analysis based on a pair-wise comparison in patients who achieved the same in-study blood pressure level in both treatment arms, making the comparison between valsartan and amlodipine more true to the original hypothesis.(7) In this subanalysis, it was statistically possible to compensate for the fact that the blood pressure control during the whole study period was worse in the valsartan-based treatment arm than in the amlodipine arm.
The results show that valsartan had a significantly better effect than amlodipine in preventing CHF for the same degree of blood pressure control (HR 0.81 [0.66–0.99]), but this post-hoc subanalysis has also been criticised by some researchers for not keeping to the main trial outcome.
Data from the VALUE trial support a prompt and vigorous blood pressure control in high-risk patients with hypertension.(12,13) In most patients, particularly in patients with diabetes (where more strict blood pressure criteria and treatment goals should be applied), good blood pressure control can be achieved through combination drug treatment.(14) This combination treatment can include one agent blocking the renin–angiotensin system (RAS) if one of the goals is the prevention of diabetes in risk patients (such as patients with metabolic syndrome). Supportive evidence for this strategy can be found in the results of the VALUE trial,(6) as well as in the CAPPP,(11) HOPE(15) and LIFE(9) trials. No comparative study is currently available in hypertension treatment to decide whether an ACE inhibitor or an ARB is the best choice of drug therapy for blocking the RAS. Therefore, factors such as price, adverse effects and medical history (diabetes, CHF or nephropathy) have to be evaluated for the final decision on which drug to choose.
In some severe cases, it could also be expected that the combination of an ACE inhibitor and an ARB is of special relevance – for example, in preventing diabetic nephropathy in some high-risk patients. This was evaluated in the CAndesartan and Lisinopril Microalbuminuria (CALM) trial, which concluded that a combination of two RAS-blocking agents was superior to either of them used alone.(16)
The VALUE trial provided interesting lessons, although it did not exactly follow the route originally designed. The main outcome of cardiac disease did not differ between the treatment groups. Unequal reductions in blood pressure might account for the differences observed between the groups in cause-specific outcomes. These findings emphasise the importance of prompt blood pressure control in high-risk hypertensive patients.
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European Society of Cardiology
European Society of Hypertension