A Prevalent Condition of Heart Failure
In the developed world the prevalence of heart failure is high and is increasing. In the US alone, it is estimated that 4.8 million Americans have heart failure. In the US, there are estimated to be 400,000 new cases each year.
A Growing Burden
Increasing prevalence, hospitalizations and deaths have made heart failure a major healthcare problem. Half of all patients diagnosed with heart failure will be dead within 5 years. Despite a decrease in mortality for most cardiovascular diseases (stroke, coronary heart disease), the mortality associated with heart failure is increasing. The trend is expected to increase further as the population ages.
An Economic Burden
The cost of heart failure is high in developed countries and represent 1-2 % of total healthcare spend (e.g. in US, UK, France, New Zealand and Sweden). The annual cost of heart failure to society in the US alone is estimated to be $ 22.5 billion. Of this almost $ 22.5 billion, almost 69 % is spent on hospital/nursing home costs. About 10 % of the total cost of heart failure is due to lost productivity from morbidity and mortality. Only around 5 % of costs are related to drugs.
Usual Treatment Today
Aims of Heart Failure Management are to improve symptoms by:
- Diuretics
- Digoxin
- ACE inhibitors
And, to improve survival by:
- ACE Inhibitors
- Beta-blockers
- Oral nitrates plus hydralazine
- Spironolactone (Davies et al. BMJ 2000; 320: 428-431)
Diuretics and digoxin may be effective in providing symptomatic relief but there is no direct evidence that either confer prognostic benefits in patients with heart failure.
ACE inhibitors have been considered the cornerstone of treatment in patients with all grades of symptomatic heart failure and in patients with asymptomatic left ventricular dysfunction. ACE inhibitors have consistently shown beneficial effects on mortality, morbidity and QOL in large scale trials.
More recently beta-blockers have been shown in several trials to improve survival
Heart Failure: Mortality Remains High
- ACE-I: risk reduction 35 % of mortality and hospitalizations. (Davies et al. BMJ 2000; 320: 428-431)
- Beta-blockers: risk reduction 38 % of mortality and hospitalizations (Gibbs et al. BMJ 2000;320:495-498)
- Oral nitrates and hydralazine: benefit vs. placebo; inferior to enalapril (mortality)
Several large clinical trials have shown ACE inhibitor treatments to reduce mortality in heart failure patients with mild, moderate or severe heart failure. The benefits from ACE inhibitors appear to be independent of age, sex, use of diuretics, aspirin and beta-blockers. Based on the clinical studies, ACE inhibitors and b blockers are recommended as cornerstone treatment for heart failure. Despite the reduction in mortality with ACE inhibitor therapy, mortality rates remain unacceptably high. Mortality in large clinical trials is close to 40 % over a four-year period.
Blockade of RAS
Angiotensin II is the central molecule of the RAS, with a multitude of actions. Both the antihypertensive and the protective effects of RAS modulators are related to their influence on angiotensin II actions. ACE inhibitors block the conversion of angiotensin I to angiotensin II and also have other substrates including bradykinin, substance P, neurotensin, enkephalin, LHRH, N-acetyl-Ser-Asp-Lys-Pro. The effect on kinins is suggested to be responsible for the cough associated with ACE inhibitors. ACE inhibitors do not block the conversion of Angiotensin I to Angiotensin II by alternative enzymes prominent in heart tissue, such as chymase. Angiotensin II receptor blockers such as valsartan block the action of Angiotensin II directly at its receptor, regardless of synthesis pathway.
Role of AT1 and AT2 Receptors
In heart failure, angiotensin II activity may play a pathological role. The deleterious effects of angiotensin II are mediated via the AT1 receptor subtype. There is also accumulating evidence that many of the more beneficial actions of angiotensin II are mediated via the AT2 receptor. Therefore, selective blockade of the effect of angiotensin II at the AT1 receptor level (whilst leaving the AT2 receptor free for angiotensin II stimulation) may be expected to offer advantages over non specific blockade of the renin angiotensin system (e.g. by ACE inhibitors).
Angiotensin II Levels Increase Over Time Despite ACEI
Reasons for high mortality rates despite ACE inhibitors may be:
- Levels of angiotensin II do not stay low during long-term ACE inhibitor treatment. Elevated angiotensin II levels in the ventricles may contribute to volume-overloaded cardiac hypertrophy. In the study by Biollaz et al, patients were given ACE inhibitor treatment upon hospitalization and angiotensin II levels were monitored for 6 months.
- Alternative pathways exist for angiotensin II formation
Valsartan: Significant Benefits in Heart Failure
Valsartan may provide beneficial cardiac effects in patients with congestive heart failure (CHF). In a hemodynamic study in 112 patients with chronic stable congestive heart failure previously untreated with ACE inhibitors, Mazayev showed that valsartan treatment led to a greater increase in cardiac output than lisinopril.
The preclinical indications of benefits from adding valsartan to ACE inhibitor treatment have been shown to be valid for man. In the hemodynamic study by Baruch et al, the study population was relatively small (n=83) and mortality was not an endpoint. Nevertheless, the addition of valsartan to background ACE inhibitor therapy had additional acute and long-term (28 days) effects on pulmonary capillary artery wedge pressure and diastolic pulmonary artery pressure.
In the study by Baruch et al, valsartan added to background ACE inhibitor treatment led to additional reductions in aldosterone and plasma norepinephrine levels. These hormones contribute to hypertension, through stimulated Na+ and water retention, and to vasoconstriction. A reduction would be expected to have protective effects in heart failure.
Valsartan Heart Failure Trial
- Long-term cardiac morbidity & mortality trial
- Chronic stable heart failure patients
- Valsartan added to usual heart failure therapy (ACE-I; diuretics; digoxin; beta blockers)
Val-HeFT was a large morbidity and mortality trial, designed as a real-life trial mimicking daily heart failure treatment in the physician’s office. Val-HeFT is the first trial to study the benefits from valsartan added to patients’ usual therapy for heart failure.
The hypothesis was that valsartan would add incremental benefits to the established benefits of standard treatments.
- 5,010 patients of 300 centers from 16 countries with chronic stable heart failure (NYHA class II - IV) confirmed on echocardiography.
- Ejection fraction: <> 2.9 cm/m2.
Val-HeFT Design
Val-HeFT was a double-blind, randomized, placebo controlled, parallel group trial. Valsartan was added to usual heart-failure therapy in a forced-titration scheme with doses of 40, 80 and 160 mg bid. Eighty per cent of patients received maximum study dose drug levels. The mean valsartan daily dose was about 240 mg. The follow-up period was 1.5 to 3.5 years with the primary endpoint of time to death or first morbid event.
Primary Efficacy Endpoints
- All cause mortality (time to death)
- Combined all cause mortality and morbidity (time to event), including all cause mortality, sudden death with resuscitation, hospitalization for heart failure, and need for therapeutic doses of intravenous inotropic or vasodilating agent for at least 4 hours.
- Alpha is equally split between both primary endpoints.
Val-HeFT was a fixed-information mortality trial and was planned to continue until a defined number (906) of deaths had occurred. An important feature of Val-HeFT was that the trial was prospectively designed to address two primary endpoints, which were of equal weight. Statistical analysis was based on an overall significance level of alpha less than equal 0.05 with an adjustment made for the two primary endpoints. Each primary end-point therefore had to reach a significance of less than equal 0.02532. Thus the criteria for a positive result were twice as robust for each endpoint.
Major Secondary Efficacy Endpoints
- Disease progression: NYHA classification, heart failure signs and symptoms
- Cardiac structure and function: left ventricular internal end-diastolic diameter; ejection fraction
- Quality of life: Minnesota living with heart failure and euroqol quality of life questionnaires
In addition to the main study there are several sub-studies looking at:
- The percentage of patients with more than 5 ventricular tachycardia events or sudden death (designed to detect a prevalence rate reduction of 30 % or more for the valsartan treatment group).
- The effect of treatment on performance in the six-minute walk test.
- The change from baseline in LV end-systolic volume.
Together, these data will provide new insights in the pathophysiology of heart failure
Inclusion Criteria
- Men and women more than equal 18 years
- Chronic stable heart failure (NYHA class II-IV)
- Echocardiographic parameters: ejection fraction less than 40 % and LV diameter (end-diastolic) more than 2.9 cm/m2.
Major Exclusion Criteria
The major exclusion criteria in Val-HeFT were the standard exclusion criteria for a clinical heart-failure trial, following clinical practice.
- Significant primary mitral valve disease or obstructive lesion of LV outflow.
- MI, unstable angina, syncope, CVA, cardiac surgery, PTCA in previous 3 months.
- Chronic Arterial Disease likely to need CABG / PTCA.
- Rapidly deteriorating heart failure.
- Heart transplant or awaiting transplant.
- Right heart failure due to pulmonary disease.
- Class 1c anti-arrhythmics, intravenous inotropes, or intravenous vasodilators in previous 3 months.
Baseline Characteristics
The Val-HeFT population was generally representative of patients with heart failure in industrialized countries. The study population was slightly younger than the general heart-failure patient population (70 ± 10.8 years in the Framingham Heart Study).
In Val-HeFT, as in most studies of heart failure, more men than women were enrolled. Only 20 % of the Val-HeFT populations were women while epidemiologically about the same proportion of women as men have heart failure. Nevertheless, the number of women in Val-HeFT represents one of the largest populations of women in a heart failure trial to date. Women were slightly more symptomatic than men based on NYHA class, signs and symptoms, although age and EF were comparable. The prevalence and severity of heart failure increases with each decade of life. In Val-HeFT, the proportion of patients with NYHA class III was greater among patients more than 65 years.
The treatment in Val-HeFT was optimal and not representative of the average heart failure population, both for ACE inhibitor and b-blocker treatment. For example, worldwide, less than 10 % of heart failure patients are discharged from hospitals on beta-blocker therapy and less than 50 % of heart-failure patients are prescribed ACE inhibitors.
Primary Endpoint Analysis
Val-HeFT showed a highly significant difference for the primary endpoint combined all-cause morbidity and mortality. The event rate for patients receiving valsartan in addition to the usual therapy for heart failure was 28.8 %, compared with 32.1 % for placebo. The 95 % confidence interval for relative risk was 0.79-0.96. This translates into a highly significant reduction in relative risk of all-cause morbidity and mortality of 13 %, with a p=value of 0.009.
All Cause Mortality
Valsartan added to usual therapy, including ACE inhibitors, had no statistically significant effect on all-cause mortality (p=0.800). This was not unexpected as patients were already receiving usual therapy including optimal doses of ACE inhibitors and b-blockers. The event rate for the placebo group was only around 9 %, which was lower than in any comparable pervious heart-failure trials. To demonstrate a further improvement in mortality below 9% would have implied an almost unprecedented effect from adding valsartan to usual therapy.
Val-HeFT included two primary endpoints: all-cause mortality and the combined endpoint of all-cause mortality and morbidity. The two primary endpoints (all cause mortality and combined all-cause mortality and morbidity) were pre-specified with appropriate statistical adjustments being defined a priori. Because there were two primary endpoints, the statistical requirements for success were high. The alpha value had to be split between the two endpoints. There was a 13.3% reduction in the combined endpoint all-cause mortality and morbidity (p =0.009).
Combined All Cause Mortality and Morbidity
Adding valsartan to usual therapy, including ACE inhibitors, led to a statistically significant reduction in the combined endpoint all-cause mortality and morbidity. The relative risk reduction was 13% (p=0.009).
Secondary Endpoint Analysis
There was a large reduction (27 %) in relative risk for heart-failure hospitalizations when valsartan was added to usual heart-failure therapies. This reduction was statistically highly significant (p=0.00001). Reductions in hospitalizations have major impacts on public health and health-care costs. About one million Americans were hospitalized in the year 2000 for heart failure. Thus a reduction of 27 % in hospitalizations would lead to substantial savings for society and invaluable reductions in personal suffering for heart-failure patients.
Heart Failure Hospitalization
The significant reduction in risk for heart-failure hospitalization from adding valsartan to usual heart-failure therapy, has implications for healthcare costs, as the cost of heart failure represent 1-2 % of total spent on healthcare in developed countries such as the US, UK, France, New Zealand and Sweden.
A reminder: the annual cost of heart failure to society in the US alone is estimated to be $ 22.5 billion. Of the almost $ 22.5 billion spent yearly on heart failure in the US, almost 69 % is spent on hospital/ nursing home costs. Only about 5 % of costs are related to drugs.
NYHA Class and Signs / Symptoms at Endpoint
There were significant improvements from valsartan in NYHA classification signs and symptoms. Significant improvements were also seen in fatigue, edema and RALES. All these benefits would be expected to be reflected in patients’ assessment of quality of life for those receiving valsartan compared with patients on placebo.
Secondary Variables Change From Baseline
For the secondary endpoint, quality of life, assessed by the Minnesota Living With Heart Failure (MLHF) score, valsartan (added to patients’ usual therapy including ACE inhibitors) led to significantly higher quality of life assessments compared with placebo (p=0.005 for differences between treatments). The MLHF provides an overall total score as well as physical and emotional sub-scale scores relating how persons with heart failure perceive how their condition has affected the quality of their lives in the past month. An increased score indicates worsening quality of life. The beneficial effects from valsartan have important implications for compliance with treatment, a key issue with heart-failure therapies. For the secondary endpoint ejection fraction, valsartan added to usual therapy likewise led to significant benefits compared with placebo (p=0.001 for difference between treatments).
Combined Morbidity and Mortality in Subgroups
Subgroup analyses are done to check for consistency of results, but it should be noted that Val-HeFT was not designed or powered to make any definitive conclusions from any subgroup analysis. Subgroup results must be interpreted cautiously and considered as exploratory and hypothesis-generating in nature.
Subgroup analyses in Val-HeFT demonstrated consistency of results. Specifically, the beneficial effect of valsartan on combined all-cause mortality and morbidity was generally consistent across predefined patient subgroups. There were no significant differences in effectiveness between age groups or genders.
The greatest benefits from valsartan were seen in groups not concurrently receiving ACE inhibitors. Patients receiving ACE inhibitors also demonstrated a reduction in combined risk with valsartan. The small subset of patients receiving b blockers without ACE inhibitors demonstrated a clear trend in favor of valsartan. In patients receiving receiving both b-blockers and ACE inhibitors however, there was a trend favoring placebo, with the effect being limited to the group of patients receiving both b-blockers and ACE inhibitors at baseline. These findings were not statistically significant.
The data indicate that valsartan may be used effectively either alone, or in combination with ACE inhibitors or b blockers.
Combined All Cause Mortality and Morbidity: Sub-Group Without ACEI Background Therapy
A subgroup analysis in patients who did not receive ACE-inhibitor treatment, showed that in these patients valsartan has a major effect on all-cause morbidity and mortality, reducing risk by 44.5 % (p=0.0002). The curves started to separate already after 3 months and the benefits continued over the whole duration of the study. Although only a subgroup analysis, the strong effect demonstrates good efficacy of valsartan.
Patients in Val-HeFT received an optimized treatment with 93% of patients on ACE inhibitors, which does not represent current real heart failure treatment. On a worldwide base only about 50 % of patients receive an ACE inhibitor; thus this subgroup analysis from Val-HeFT demonstrated beneficial effects for the majority of heart-failure patients in the real world.
Summary of Results
- Valsartan exerted a neutral effect on mortality but significantly reduced the combined endpoint of mortality and morbidity by 13.3 % in patients with heart failure.
- Valsartan significantly reduced heart-failure hospitalizations by 27.5 %.
- Valsartan significantly improved NYHA functional class, ejection fraction and signs and symptoms.
- Valsartan added to usual therapy led to significant improvements in quality of life compared with placebo.
- In a subpopulation of patients treated with valsartan and both an ACE inhibitor and a b blocker, a trend favoring placebo was observed. However, subgroup results must be interpreted cautiously and considered as exploratory and hypothesis-generating in nature.
Conclusion
Valsartan is an effective treatment to reduce combined morbidity and mortality in patients receiving usual therapy for heart failure.
Adapted from Lecture Note on Valsartan Heart Failure Trial by dr. Moch. Fathoni, Departement of Cardiology, Medical Faculty, Sebelas Maret University.
Posted by: emjinain