The VALsartan In Diastolic Dysfunction (VALIDD) Trial
The VALsartan In Diastolic Dysfunction (VALIDD) Trial
Hypertension is believed to be the single greatest factor influencing the development of heart failure, particularly heart failure with preserved ejection fraction, also known as diastolic heart failure. Progressive diastolic dysfunction characterized by abnormalities of ventricular filling, including increased diastolic distensibility and impaired relaxation, is believed to represent a key pathophysiologic intermediate between hypertension and diastolic heart failure. About 50% of hypertensive patients are estimated to have diastolic dysfunction, making it an attractive target for heart failure prevention. Although treatment of hypertension can regress left ventricular hypertrophy (LVH), the effect of antihypertensive treatment on myocardial function, particularly diastolic function, is less well understood.
The VALsartan In Diastolic Dysfunction (VALIDD) trial was based on the hypothesis that inhibiting the renin-angiotensin-aldosterone system (RAAS) with an angiotensin receptor blocker (ARB) would improve diastolic function in hypertensive patients to a greater extent than other antihypertensive therapies, possibly by greater regression of LVH or reduction of LV mass or myocardial fibrosis. However, the results of the trial, presented on behalf of the investigators by Scott D. Solomon, MD (Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts), failed to demonstrate any significant benefit for valsartan in this regard over other antihypertensive agents, with all antihypertensive regimens, including those without RAAS inhibition, equally effective in improving diastolic function.
Dr. Solomon believes that the failure to show any benefit of the ARB over other blood pressure-lowering drugs may have been due to the particular patients enrolled in this study, none of whom had severe hypertension and who showed a low incidence of LVH. "We know from large outcomes studies that inhibiting RAAS is tremendously beneficial and has been proven to be more beneficial than other methods of lowering blood pressure in myocardial infarction and in heart failure," he said. "We believe that in patients with mild hypertension we might not have been able to see that effect because they do not have enough structural heart damage."
The VALIDD trial, which was supported by Novartis (Basel, Switzerland), was designed as a double-blind, randomized, placebo-controlled trial comparing the effects of valsartan or placebo added to standard antihypertensive therapy on echocardiographic measures of diastolic function in patients with hypertension and evidence of diastolic dysfunction. Diastolic function in VALIDD was measured by tissue Doppler imaging, a relatively new echocardiographic technique that assesses the velocity of myocardial wall motion. Patients who entered into VALIDD were men and women aged ≥ 45 years with stage I or II hypertension (blood pressure ≥ 140/90 mm Hg). All patients were screened at baseline for diastolic dysfunction on the basis of mitral annular relaxation velocities. Age-based cutoffs for mitral annular relaxation velocity were chosen because this measure is known to be age-dependent. Diastolic dysfunction was considered present if the early diastolic mitral annular relaxation velocity (E′) was:
Exclusion criteria for the study were:
Out of a total of 482 patients who were screened at 41 centers in the United States and Canada, 384 fulfilled the entry criteria. Their average age was 61 years; about 50% were women; and 12% were African American. Average blood pressure at baseline was 144/86 mm Hg; about 12% of patients were diabetic; and about 52% had a history of hyperlipidemia. Over 75% of patients were taking antihypertensive medications, whereas the others were previously untreated. Less than 4% showed LVH by echocardiographic or electrocardiographic criteria, and the average LV ejection fraction was 57%.
Patients were randomized (including stratification based on concomitant/no concomitant medication) to receive either valsartan 160 mg, uptitrated to 320 mg, or placebo once daily, in addition to their standard concomitant therapy (if any) administered at the usual dosage. Blood pressure was treated to a target of < 135/80 mm Hg with an add-on strategy starting with a diuretic followed by a calcium channel blocker (CCB) or a beta-blocker, then an alpha-blocker, but excluding ARBs, ACE inhibitors, and aldosterone antagonists. All patients were followed for 38 weeks during which they were evaluated at 1- to 6-week intervals.
During the study, patients in the placebo arm received significantly more concomitant antihypertensive medications, particularly diuretics and CCBs, than those in the valsartan arm: diuretics, 69.3% in the valsartan group vs 81.1% in the non-RAAS group (P = .01); CCBs, 51% in the valsartan group vs 77.7% in the non-RAAS group (P < .001). Over 9 months of treatment, mean blood pressure declined in the valsartan group from 143/84 to 129/78 mm Hg, and in the placebo group from 144/87 to 134/82 mm Hg. Blood pressure decreases at the end of the trial did not differ significantly between the 2 treatment groups.
VALIDD was the first large multicenter trial to study diastolic function as a primary endpoint. At the end of 38 weeks, repeat echocardiography in 341 patients who completed the trial revealed that E′ increased significantly in both treatment groups, but the increases did not differ between the valsartan and placebo arms ( Table 1 ).
There were no differences between the 2 treatment groups in secondary efficacy endpoints, except for a significant improvement in isovolumic relaxation time in the valsartan arm compared with the placebo arm ( Table 2 ). Small but significant decreases were seen in LV mass index and systolic wall thickening in each group, but these did not differ significantly between the 2 treatment groups.
The reduction in systolic blood pressure at time of echocardiography was inversely related to the improvement in E′. Even after adjustment for baseline blood pressure, baseline E′, age, and treatment group, the relationship between blood pressure lowering and improvement in diastolic function remained significant (P = .01). The relationship appeared to be nonlinear, with patients having a > 10 mm Hg reduction in systolic blood pressure showing the greatest improvement in relaxation velocity.
Dr. Solomon acknowledged several limitations of the study. Although the observed blood pressure and LV mass index were reduced in both groups, it was not possible to determine whether the improvement in diastolic function observed in VALIDD required changes in myocardial structure or were a direct result of reduced afterload and might have been observed in a shorter time period. It is possible that RAAS inhibition would have shown greater relative benefit in a population with more severe hypertension or greater prevalence of LVH population. The relationship between the degree of improvement in diastolic function, a surrogate measure, and clinical outcomes or measures of clinical benefit remains to be determined by ongoing and future studies.
Dr. Solomon suggested that if he and his coinvestigators had selected a patient population with more LVH and fibrosis, they might have seen different results, based on evidence that inhibiting RAAS can be of greater benefit in patients with more hypertrophy and more fibrosis. "Clearly this was a very early-stage population, so we were seeing a hemodynamic benefit, but not the full potential benefit of blood pressure lowering with this approach because this patient population turned out to be so benign," Dr. Solomon theorized. "If we had managed to find more hypertrophy, it is very possible that we would have seen greater benefit."
All the trends were in favor of the ARB even though there was a small blood pressure difference between the 2 arms. He noted that with longer term therapy, many outcome studies have demonstrated benefits of RAAS inhibition in more advanced disease populations. He and the VALIDD team believe that their findings suggest that one of the benefits of treating hypertension may be to improve diastolic function, even in patients with mild hypertension, and that they offer a potential mechanism by which lowering of blood pressure may reduce the risk of manifesting heart failure. When diastolic dysfunction is present in patients with mild-to-moderate hypertension, it may represent an early measure of end-organ damage that can precede LVH in patients with hypertension. However, the relationship between the degree of improvement in diastolic function, a surrogate measure, and clinical outcomes or measures of clinical benefit remains to be determined by ongoing and future studies.
Dr. Solomon noted that the VALIDD results add mechanistic support to studies, such as the Candesartan in Heart Failure -- Assessment of Mortality and morbidity (CHARM)-Preserved study. However, whether there is incremental benefit to blood pressure lowering by blocking the RAAS will not be known until data become available from additional trials in more diseased populations. Larger outcome studies, eg, the Irbesartan in Heart Failure with Preserved Systolic Function (I-PRESERVE) and Treatment Of Preserved Cardiac function heart failure with an Aldosterone anTagonist (TOPCAT) trials, are investigating RAAS inhibition in heart failure patients with preserved ejection fraction.
Dr. Solomon and his colleagues are performing a follow-up trial to VALIDD. The EXforge aggressive Control of hypertension to Evaluate Efficacy in Diastolic dysfunction (EXCEED) trial, also sponsored by Novartis, is enrolling patients with more severe hypertension who are given a very aggressive blood pressure-lowering strategy to reduce blood pressure to well below the current guideline targets. This open-label trial is testing a blood pressure-lowering strategy rather than a particular type of medication, Dr. Solomon explained. Patients will receive a valsartan plus amlodipine combination (Exforge, Novartis) in 2 different doses to get very aggressive or less aggressive blood pressure lowering over 6 months. The trial is currently enrolling patients, and the investigators expect to have the results in late 2008.
Hypertension is believed to be the single greatest factor influencing the development of heart failure, particularly heart failure with preserved ejection fraction, also known as diastolic heart failure. Progressive diastolic dysfunction characterized by abnormalities of ventricular filling, including increased diastolic distensibility and impaired relaxation, is believed to represent a key pathophysiologic intermediate between hypertension and diastolic heart failure. About 50% of hypertensive patients are estimated to have diastolic dysfunction, making it an attractive target for heart failure prevention. Although treatment of hypertension can regress left ventricular hypertrophy (LVH), the effect of antihypertensive treatment on myocardial function, particularly diastolic function, is less well understood.
The VALsartan In Diastolic Dysfunction (VALIDD) trial was based on the hypothesis that inhibiting the renin-angiotensin-aldosterone system (RAAS) with an angiotensin receptor blocker (ARB) would improve diastolic function in hypertensive patients to a greater extent than other antihypertensive therapies, possibly by greater regression of LVH or reduction of LV mass or myocardial fibrosis. However, the results of the trial, presented on behalf of the investigators by Scott D. Solomon, MD (Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts), failed to demonstrate any significant benefit for valsartan in this regard over other antihypertensive agents, with all antihypertensive regimens, including those without RAAS inhibition, equally effective in improving diastolic function.
Dr. Solomon believes that the failure to show any benefit of the ARB over other blood pressure-lowering drugs may have been due to the particular patients enrolled in this study, none of whom had severe hypertension and who showed a low incidence of LVH. "We know from large outcomes studies that inhibiting RAAS is tremendously beneficial and has been proven to be more beneficial than other methods of lowering blood pressure in myocardial infarction and in heart failure," he said. "We believe that in patients with mild hypertension we might not have been able to see that effect because they do not have enough structural heart damage."
Trial Design
The VALIDD trial, which was supported by Novartis (Basel, Switzerland), was designed as a double-blind, randomized, placebo-controlled trial comparing the effects of valsartan or placebo added to standard antihypertensive therapy on echocardiographic measures of diastolic function in patients with hypertension and evidence of diastolic dysfunction. Diastolic function in VALIDD was measured by tissue Doppler imaging, a relatively new echocardiographic technique that assesses the velocity of myocardial wall motion. Patients who entered into VALIDD were men and women aged ≥ 45 years with stage I or II hypertension (blood pressure ≥ 140/90 mm Hg). All patients were screened at baseline for diastolic dysfunction on the basis of mitral annular relaxation velocities. Age-based cutoffs for mitral annular relaxation velocity were chosen because this measure is known to be age-dependent. Diastolic dysfunction was considered present if the early diastolic mitral annular relaxation velocity (E′) was:
< 10 cm/second for patients aged 45-55 years;
< 9 cm/second for patients aged 55-65 years; and
< 8 cm/second for patients aged ≥ 66 years.
Exclusion criteria for the study were:
Severe (≥ stage III) arterial hypertension;
LV ejection fraction ≤ 50%;
Serum creatinine > 2/5 mg/dL;
Uncontrolled diabetes mellitus (glycated hemoglobin [HbA1C] > 8.5%)
Heart failure within the past year; and
Prior intolerance or contraindication to an angiotensin-converting enzyme (ACE) inhibitor or an ARB.
Out of a total of 482 patients who were screened at 41 centers in the United States and Canada, 384 fulfilled the entry criteria. Their average age was 61 years; about 50% were women; and 12% were African American. Average blood pressure at baseline was 144/86 mm Hg; about 12% of patients were diabetic; and about 52% had a history of hyperlipidemia. Over 75% of patients were taking antihypertensive medications, whereas the others were previously untreated. Less than 4% showed LVH by echocardiographic or electrocardiographic criteria, and the average LV ejection fraction was 57%.
Patients were randomized (including stratification based on concomitant/no concomitant medication) to receive either valsartan 160 mg, uptitrated to 320 mg, or placebo once daily, in addition to their standard concomitant therapy (if any) administered at the usual dosage. Blood pressure was treated to a target of < 135/80 mm Hg with an add-on strategy starting with a diuretic followed by a calcium channel blocker (CCB) or a beta-blocker, then an alpha-blocker, but excluding ARBs, ACE inhibitors, and aldosterone antagonists. All patients were followed for 38 weeks during which they were evaluated at 1- to 6-week intervals.
Results
During the study, patients in the placebo arm received significantly more concomitant antihypertensive medications, particularly diuretics and CCBs, than those in the valsartan arm: diuretics, 69.3% in the valsartan group vs 81.1% in the non-RAAS group (P = .01); CCBs, 51% in the valsartan group vs 77.7% in the non-RAAS group (P < .001). Over 9 months of treatment, mean blood pressure declined in the valsartan group from 143/84 to 129/78 mm Hg, and in the placebo group from 144/87 to 134/82 mm Hg. Blood pressure decreases at the end of the trial did not differ significantly between the 2 treatment groups.
VALIDD was the first large multicenter trial to study diastolic function as a primary endpoint. At the end of 38 weeks, repeat echocardiography in 341 patients who completed the trial revealed that E′ increased significantly in both treatment groups, but the increases did not differ between the valsartan and placebo arms ( Table 1 ).
There were no differences between the 2 treatment groups in secondary efficacy endpoints, except for a significant improvement in isovolumic relaxation time in the valsartan arm compared with the placebo arm ( Table 2 ). Small but significant decreases were seen in LV mass index and systolic wall thickening in each group, but these did not differ significantly between the 2 treatment groups.
The reduction in systolic blood pressure at time of echocardiography was inversely related to the improvement in E′. Even after adjustment for baseline blood pressure, baseline E′, age, and treatment group, the relationship between blood pressure lowering and improvement in diastolic function remained significant (P = .01). The relationship appeared to be nonlinear, with patients having a > 10 mm Hg reduction in systolic blood pressure showing the greatest improvement in relaxation velocity.
Limitations and Explanations
Dr. Solomon acknowledged several limitations of the study. Although the observed blood pressure and LV mass index were reduced in both groups, it was not possible to determine whether the improvement in diastolic function observed in VALIDD required changes in myocardial structure or were a direct result of reduced afterload and might have been observed in a shorter time period. It is possible that RAAS inhibition would have shown greater relative benefit in a population with more severe hypertension or greater prevalence of LVH population. The relationship between the degree of improvement in diastolic function, a surrogate measure, and clinical outcomes or measures of clinical benefit remains to be determined by ongoing and future studies.
Dr. Solomon suggested that if he and his coinvestigators had selected a patient population with more LVH and fibrosis, they might have seen different results, based on evidence that inhibiting RAAS can be of greater benefit in patients with more hypertrophy and more fibrosis. "Clearly this was a very early-stage population, so we were seeing a hemodynamic benefit, but not the full potential benefit of blood pressure lowering with this approach because this patient population turned out to be so benign," Dr. Solomon theorized. "If we had managed to find more hypertrophy, it is very possible that we would have seen greater benefit."
All the trends were in favor of the ARB even though there was a small blood pressure difference between the 2 arms. He noted that with longer term therapy, many outcome studies have demonstrated benefits of RAAS inhibition in more advanced disease populations. He and the VALIDD team believe that their findings suggest that one of the benefits of treating hypertension may be to improve diastolic function, even in patients with mild hypertension, and that they offer a potential mechanism by which lowering of blood pressure may reduce the risk of manifesting heart failure. When diastolic dysfunction is present in patients with mild-to-moderate hypertension, it may represent an early measure of end-organ damage that can precede LVH in patients with hypertension. However, the relationship between the degree of improvement in diastolic function, a surrogate measure, and clinical outcomes or measures of clinical benefit remains to be determined by ongoing and future studies.
Additional Studies
Dr. Solomon noted that the VALIDD results add mechanistic support to studies, such as the Candesartan in Heart Failure -- Assessment of Mortality and morbidity (CHARM)-Preserved study. However, whether there is incremental benefit to blood pressure lowering by blocking the RAAS will not be known until data become available from additional trials in more diseased populations. Larger outcome studies, eg, the Irbesartan in Heart Failure with Preserved Systolic Function (I-PRESERVE) and Treatment Of Preserved Cardiac function heart failure with an Aldosterone anTagonist (TOPCAT) trials, are investigating RAAS inhibition in heart failure patients with preserved ejection fraction.
Dr. Solomon and his colleagues are performing a follow-up trial to VALIDD. The EXforge aggressive Control of hypertension to Evaluate Efficacy in Diastolic dysfunction (EXCEED) trial, also sponsored by Novartis, is enrolling patients with more severe hypertension who are given a very aggressive blood pressure-lowering strategy to reduce blood pressure to well below the current guideline targets. This open-label trial is testing a blood pressure-lowering strategy rather than a particular type of medication, Dr. Solomon explained. Patients will receive a valsartan plus amlodipine combination (Exforge, Novartis) in 2 different doses to get very aggressive or less aggressive blood pressure lowering over 6 months. The trial is currently enrolling patients, and the investigators expect to have the results in late 2008.
