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European Journal of Heart Failure 2003 5(4):537-544; doi:10.1016/S1388-9842(03)00112-0
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© 2003 European Society of Cardiology

VALsartan In Acute myocardial iNfarcTion (VALIANT) trial: baseline characteristics in context

Eric J. Velazqueza,*, Marc A. Pfefferb, John V. McMurrayc, Aldo P. Maggionid, Jean-Lucien Rouleaue, Frans Van de Werff, Lars Koberg, Harvey D. Whiteh, Karl Swedbergi, Jeffrey D. Leimbergera, Paul Galloj, Mary Ann Sellersa, Susan Edwardsj, Marc Henisj, Robert M. Califfa and for the VALIANT Investigators

a Division of Cardiology, Department of Medicine, Duke University Medical Center and the Duke Clinical Research Institute 2400 Pratt Street, Durham, NC 27715, USA
b Cardiovascular Division Brigham and Women's Hospital, Boston, MA, USA
c Clinical Research Initiative in Heart Failure University of Glasgow, Glasgow, Scotland, UK
d ANMCO Research Center Florence, Italy
e Division of Cardiology University of Toronto, Toronto, ON, Canada
f Leuven Coordinating Center Leuven, Belgium
g Rigshospitalet, Copenhagen Denmark
h Green Lane Hospital Auckland, New Zealand
i Sahlgrenska Hospital Göteborg, Sweden
j Novartis Pharmaceutical Corporation East Hanover, NJ, USA

* Corresponding author. Tel.: +1-919-668-8041; fax: +1-919-668-7058 velaz002{at}mc.duke.edu


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 Appendix A. Enrollment criteria...
 References
 
Background: The VALsartan In Acute myocardial iNfarcTion (VALIANT) trial compared outcomes with: (1) angiotensin-converting enzyme inhibition (ACEI) with the reference agent captopril; (2) angiotensin-receptor blockade (ARB) with valsartan; or (3) both in patients with heart failure (HF) and/or left ventricular systolic dysfunction (LVSD) after myocardial infarction (MI).

Aims: A goal of this active-control trial was to simulate conditions that would lead current practitioners to use ACEIs. Thus, we compared characteristics of VALIANT patients with those of patients in placebo-controlled trials that established ACEIs as standard treatment.

Methods and Results: We collected demographic, clinical, medication and imaging information from 14703 patients in 24 countries. This high-risk population was a median 65.8 years old, and 31.1% were female. Most (51.8%) showed imaging evidence of LVSD at enrollment. Most (72%) had Killip class≥II HF. Patients received evidence-based therapies at rates similar to those of contemporary MI trials and at an improved rate compared with prior placebo-controlled ACEI trials.

Conclusion: VALIANT represents the largest globally representative cohort enrolled with HF and/or LVSD after MI. Patients were similar to those in placebo-controlled ACEI trials while reflecting improvements in evidence-based care. With enrollment complete, VALIANT is poised to define the optimal strategy for renin–angiotensin system blockade after MI to improve cardiovascular outcomes.

Key Words: Angiotensin-converting enzyme • Angiotensin receptor blocker • Myocardial infarction • Left ventricular dysfunction • Heart failure • Prognosis

Received March 18, 2003; Revised July 2, 2003; Accepted July 3, 2003


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 Appendix A. Enrollment criteria...
 References
 
Patients with symptomatic heart failure (HF) and/or left ventricular systolic dysfunction (LVSD) during initial hospitalization for myocardial infarction (MI) have a high risk of death and other undesirable clinical outcomes [1,2]. Although angiotensin-converting enzyme inhibitors (ACEIs) reduce the risk of death and recurrent heart failure [3], mortality and morbidity rates remain high, both in randomized trials and in clinical practice [4]. Accordingly, development of effective new therapies, including new ways of blocking the renin-angiotensin system, remains a high priority.

Angiotensin receptor blockers (ARBs) [5] provide a different method of blocking the renin-angiotensin system; their direct mechanism of action blocks the system more completely without a direct effect on bradykinin inactivation. Theoretically, ARBs could be superior to, equal to or inferior to ACEIs in ameliorating adverse outcomes in patients with HF and/or LVSD after MI, but conclusive clinical-trial data are lacking. Furthermore, the combination of an ACEI and an ARB may provide even greater clinical benefits than either alone, by preserving the bradykinin-potentiating effects of ACEI while adding more complete angiotensin II blockade.

The VALsartan In Acute myocardial iNfarcTion (VALIANT) trial was designed to determine the relative effects of valsartan, an ARB; captopril, a proven ACEI; and their combination on mortality in patients with acute MI complicated by HF and/or LVSD. The trial called for randomization of more than 14 500 patients and a follow-up duration anticipated to encompass 2700 deaths [6]. Because VALIANT is testing for non-inferiority as well as superiority of valsartan, it was required that patients be similar to those enrolled in the three major trials that showed ACEIs to be superior to placebo after MI: the Survival And Ventricular Enlargement (SAVE) [7], Acute Infarction Ramipril Efficacy (AIRE) [8] and TRAndolapril Cardiac Evaluation (TRACE) [9] studies. In this way, ‘putative placebo’ comparisons can be drawn [10–12].

This manuscript provides an initial evaluation of the baseline characteristics of the VALIANT population and compares them with the three reference trials that form the basis for future comparisons.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusions
 Appendix A. Enrollment criteria...
 References
 
2.1. Patients
VALIANT was a prospective, multinational (24 countries), double-blind, randomized, active-control study with three parallel treatment groups. Men and women age 18 or older were randomized 12 h to 10 days after symptom onset of acute MI, defined as biomarker evidence of myocardial necrosis with a typical clinical presentation or electrocardiographic changes (see Appendix A). Eligible patients also had either transient or persistent HF, defined by clinical signs (pulmonary edema, bilateral posttussive rales in at least the lower third of the lung fields, or an S3 gallop with persistent tachycardia), radiological evidence of pulmonary venous congestion with interstitial or alveolar edema and/or evidence of LVSD after the qualifying MI [6]. Acceptable evidence of LVSD included an ejection fraction ≤35% on echocardiography or contrast angiography, ejection fraction ≤40% on radionuclide angiography, or a wall-motion index consistent with an ejection fraction ≤35% on echocardiography [13].

2.2. Study design
The rationale and design of the VALIANT trial, including full inclusion and exclusion criteria and the details of study-drug initiation, titration and the visit schedule, have been published [6]. Briefly, patients were randomly allocated via interactive voice–response system to one of three investigational arms in a 1:1:1 ratio: captopril alone (target dose of 50 mg three times daily), valsartan alone (target dose of 160 mg twice daily) or captopril plus valsartan (target dose of captopril 50 mg three times daily plus valsartan 80 mg twice daily). Although the use of ACEIs or ARBs before enrollment was not an exclusion criterion, patients were not to receive these therapies from at least 12 h before randomization through the period of study. The protocol otherwise did not dictate the therapies to be used, except to suggest adherence to published guidelines.

The baseline visit occurred upon randomization. Sites recorded baseline data during this initial visit for all patients, regardless of the status of study-drug dosing. The protocol suggested that titration to step 3 (captopril 25 mg three times daily, valsartan 80 mg twice daily or captopril 25 mg three times daily plus valsartan 40 mg twice daily) occur by the second visit, which was to take place at discharge or day 14 after randomization, whichever occurred first. Follow-up visits were scheduled for 1, 3, 6, 9 and 12 months after randomization and at 4-month intervals thereafter to ascertain vital signs and evaluate study endpoints, drug safety and tolerability, quality of life and use of health resources.

2.3. Statistical analysis
The statistical design of VALIANT [6] allows for superiority analyses of both valsartan arms against the captopril comparator arm and for non-inferiority analysis of valsartan alone against captopril, if we do not prove superiority. The primary efficacy outcome is all-cause mortality (time to death). The critical secondary efficacy outcome is the composite of cardiovascular mortality or emergency treatment or hospitalization for new or worsening heart failure. To accommodate all of these endpoints and ensure sufficient statistical power, we planned a total sample size of 14 500 patients with follow-up to continue until 2700 deaths had accrued.

An explicit goal of the study was to simulate the criteria that would lead a practitioner to begin ACEI therapy according to current guidelines while also enrolling a population closely matching the composite population of the SAVE, TRACE and AIRE reference studies. Thus, we compared the baseline characteristics of the VALIANT population with those of these reference trials and other relevant ongoing or recently published clinical trials of MI.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusions
 Appendix A. Enrollment criteria...
 References
 
In all, 931 sites in 24 countries on five continents enrolled 14 703 patients from 31 December, 1998 through to 30 June, 2001. Table 1 provides the distribution by country of patients enrolled. A baseline case-report form was received for each patient randomized; nevertheless, these data should be considered preliminary. Data from one site have been excluded due to procedural irregularities in obtaining informed consent at that site.


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  		Table 1 Randomized patients by region and country

 
Table 2 provides the baseline demographics and medical history. Of the patients enrolled, the mean age was 64.8 years with a median of 65.8 years, 25% were >74 years old and 31.1% were women. The cohort had high rates of standard cardiac risk factors and expected rates of non-cardiac comorbid conditions.


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  		Table 2 Baseline demographic characteristics and medical history

 
Table 3 details the characteristics of the qualifying MI and clinical findings at randomization. In all, 99.9% of the randomized population met the MI biomarker criteria. Of those randomized, 88.6% had electrocardiographic findings typical of MI (evolving ST-segment or T-wave changes, new or pathological Q waves or new left bundle–branch block). The vast majority of patients (92.7%) were reported to have had a typical clinical MI presentation.


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  		Table 3 Baseline clinical characteristics

 
Although most patients were classified as Killip class II or greater by investigators, >40% of the population was enrolled after a non-anterior MI and >30% after a non-Q-wave MI. Fig. 1 displays the interrelation of clinical signs of HF, radiographic evidence of pulmonary congestion and quantitative evidence of LVSD used to enroll the VALIANT population. A total of 51.8% of patients entered into the study met the LVSD entry criteria by the time of randomization. Of those randomized, 11.6% met all three possible HF and LVSD entry criteria, although multiple criteria were not required.


Figure 1
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  		Fig. 1 Proportions of patients with heart-failure signs and symptoms, radiographic pulmonary congestion and/or quantitative evidence of left ventricular systolic dysfunction at or before randomization.

 
The median time from MI symptom onset to randomization was 116 h (4.9 days), and 75% of VALIANT patients were enrolled within 171 h (7.1 days). Between MI symptom onset and randomization, 26.9% underwent revascularization (25.1% percutaneous intervention, 2.1% bypass surgery) and 17.4% had significant conduction-system or rhythm disturbances (Table 4).


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  		Table 4 Events occurring between the qualifying infarction and randomization

 
Investigators recorded therapies used within 12 h of symptom onset. Aspirin was given to 13 083 patients (89.0%) and β-blockers were used in 8711 patients (59.3%) in acute management of the index MI. Acute reperfusion therapy—either fibrinolysis (5170 patients, 35.2%) or percutaneous intervention (2178 patients, 14.8%)—was used in 45.7% of patients. Platelet glycoprotein IIb/IIIa integrin blockade was used in 1923 patients (13.1%). During this period, 6172 patients (42.0%) received an ACEI and 185 patients (1.3%) received an ARB.

Table 5 details the use of cardiovascular and other concomitant medications within 24 h of randomization. From the acute MI presentation to randomization, β-blocker use increased from 59.3 to 70.4%.


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  		Table 5 Concomitant medication use within 24 h of randomization

 
Most baseline characteristics, such as heart rate, diastolic blood pressure, race, mean age and Killip class were broadly comparable between VALIANT and the SAVE, AIRE and TRACE studies (Table 6). VALIANT patients were slightly older and comprised larger proportions of female and diabetic patients than the three reference studies. Table 6 also provides a comparison of the VALIANT population with another recent trial of ARB after MI, the OPtimal Trial In Myocardial infarction with the Angiotensin II Antagonist Losartan (OPTIMAAL) [14–16].


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  		Table 6 Comparison of baseline patient characteristics in VALIANT vs. placebo-controlled ACEI reference trials and recently completed trials of myocardial infarction

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusions
 Appendix A. Enrollment criteria...
 References
 
The VALIANT cohort represents the largest population of patients ever entered into a randomized controlled trial of long-term secondary prevention therapies after acute MI. Baseline data from these patients thus provide a unique opportunity to evaluate the contemporary global management of MI. The patients enrolled in VALIANT were generally similar demographically to those in other large MI trials and registries. However, VALIANT patients were slightly younger, on average, than were patients in country-specific registries [17,18] and global registries [19] and slightly older than those in recent MI trials [20] enrolling patients regardless of ST-segment deviation. The proportion of women enrolled in VALIANT (31.1%) more closely resembles their preponderance in population-based MI studies compared with previous cardiovascular trials [21]. Given the recent focus [19] on the disparity between the HF patients seen in practice (with a preponderance of elderly women) and those enrolled in trials (who tend to be younger men), the older and more-female population in VALIANT may be more clinically representative than those in previous trials of patients with HF or LVSD. Furthermore, the global applicability of trial results benefits from the balanced enrollment from multiple regions of the world.

The similarity of the VALIANT population to patients in reference trials of ACEIs after MI is of paramount importance because the VALIANT analysis plan calls for a non-inferiority analysis [22] if valsartan is not found to be superior to captopril. We elected to compare the VALIANT population characteristics with those of a pooled population constructed from patient data from the three reference trials [3]. Although the VALIANT entry criteria represent an inclusive summary of the entry criteria of the three smaller reference trials, the VALIANT population would not likely have exactly the same baseline clinical characteristics as patients enrolled in smaller trials, each of which contained only a subset of VALIANT entry criteria. Nonetheless, most baseline characteristics in VALIANT were broadly comparable with those of the pooled data from the reference studies, making a robust non-inferiority analysis feasible.

In this study, the therapies used in the short-term treatment of the index MI provide a current summary of the global approach to management of high-risk MI. The VALIANT trial, in keeping with the three reference trials, did not limit enrollment based on ST-segment deviation. The use of fibrinolysis or percutaneous intervention within 12 h of symptom onset in approximately half of the VALIANT patients, while only a subset of the population likely was eligible, thus represents an unbiased depiction of the global application of acute reperfusion therapy in patients with HF and/or LVSD shortly after MI. The fact that 13.1% of the cohort received platelet glycoprotein IIb/IIIa inhibitors shortly after MI symptom onset reflects clinician extrapolation of data from randomized trials [23,24] showing their efficacy in patients without persistent ST-segment elevation, and this finding represents an initial report on the clinical uptake of this class of agents in high-risk patients with MI.

VALIANT patients received other current medical therapy for MI, as evidenced by the high rates of concomitant aspirin (91.3%) and β-blocker (70.4%) use within 24 h of randomization. These rates were greater than those described in the reference ACEI trials, reflecting an evolution in the use of evidence-based therapies over the decade separating the different enrollment periods (see Table 6), consistent with the findings of Lamas et al. [25]. HMG CoA-reductase inhibitors (statins) also were prescribed for 34.1% of patients in VALIANT. The reference trials did not report the use of lipid-lowering drugs, presumably because the rates were very low. The higher rates of aspirin and β-blocker use, as well as the use of HMG CoA reductase inhibitors, are likely to translate into improved overall morbidity and mortality in comparison with these trials. The decreasing use of other agents, meanwhile, further highlights that the VALIANT investigators treated patients according to current, evidence-based MI guidelines [26]. For example, calcium-channel blockers were used at discharge in 42, 16 and 28% of patients randomized into the SAVE, AIRE and TRACE trials, respectively, but in only 8.6% of patients in VALIANT at randomization.

The only other large trial of an ARB vs. ACEI after MI is OPTIMAAL [14–16]. The OPTIMAAL investigators demonstrated that losartan titrated post-MI to a maximal dose of 50 mg did not provide a sustained clinical advantage over captopril at the same dose used in VALIANT. Significant differences in the design of the two trials including a more rapid increase in dosage early after MI during the critical early remodeling phase and a larger comparable maximal dose of ARB in VALIANT will clarify the relative effect of ACEIs and ARBs in the post MI setting. OPTIMAAL also differs from VALIANT due to the lack of a combination ACEI/ARB comparator. Although the Valsartan Heart Failure Trial (Val-HeFT) [27] provides some indication that the addition of valsartan to standard therapy including an ACEI in approximately 93% of patients decreased hospitalization for heart failure in a chronic heart failure patient population, it is left to VALIANT to define if combination therapy in the high-risk post MI patient population will provide additional clinical benefit beyond either an ACEI or ARB alone. There also are important differences in the numbers randomized and inclusion criteria. For example, OPTIMAAL enrolled only patients >50 years old who lived in western Europe or Scandinavia, and HF or LVSD was not required if patients had an anterior MI. Baseline dissimilarities between these two trials, such as a slightly younger average age, greater Killip class and greater proportion of patients with previous MI or diabetes in VALIANT, may reflect these different enrollment criteria. Final trial reporting will be necessary to establish whether the differences in global baseline variables resulted in significant differences in mortality risk between these two trials of ARB use after MI.

The large numbers of patients receiving aspirin and β-blockers in the three VALIANT arms will clarify the debates surrounding potentially negative interactions of ACEIs with aspirin [28,29] and of combination ACEI/ARB therapy with β-blockers [27]. The greater numbers of VALIANT patients who received combined aspirin/ACEI and ACEI/ARB/β-blocker triple therapy compared with the trials that generated questions about potential interactions will provide further information needed for clinical practice.


   5. Conclusions
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
Appendix A. Enrollment criteria...
 References
 
In conclusion, VALIANT, comparing the ARB valsartan, the ACEI captopril and their combination, is the largest trial to enroll patients with heart failure and/or left ventricular systolic dysfunction after MI. The global baseline demographics of the cohort are generally similar to reference, placebo-controlled ACEI trials and will allow putative placebo comparisons. Differences in concurrent medication use reflect an appropriate evolution in the application of evidence-based therapies in contemporary patients with MI. With the completion of randomization, VALIANT has succeeded in assembling a high-risk, post-MI cohort treated with modern, evidence-based concomitant therapies. The trial is now poised to define the optimal strategy for inhibiting the renin–angiotensin system to improve long-term survival.


   Appendix A. Enrollment criteria for acute myocardial infarction
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 Appendix A. Enrollment criteria...
References
 

  1. Increased plasma concentration of cardiac markers, defined as any of the following:
    • Total creatine kinase (CK) and CK-MB levels both above the upper limit of normal (>ULN), and one of which ≥2 times (x) ULN.
    • Total CK or CK-MB level ≥2xULN when the other is unavailable, or total CK or CK-MB level >ULN if accompanied by troponin T or I level ≥3xULN.
    • Troponin T or I level ≥5xULN when neither total CK nor CK-MB is available.

  2. Typical clinical presentation or typical electrocardiographic changes, defined as any of the following:
    • Evolving ST-segment or T-wave changes in ≥2 contiguous leads.
    • New pathological Q or QS waves in ≥2 contiguous leads.
    • New left bundle–branch block.


   Acknowledgements
 
This study was supported by a grant from Novartis Pharmaceutical Corporation, East Hanover, NJ, USA. Dr Velazquez has received research support under the Joseph C. Greenfield, Jr. Scholars Program.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 Appendix A. Enrollment criteria...
 References
 

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M. A. Pfeffer, J. J.V. McMurray, E. J. Velazquez, J.-L. Rouleau, L. Kober, A. P. Maggioni, S. D. Solomon, K. Swedberg, F. Van de Werf, H. White, et al.
Valsartan, Captopril, or Both in Myocardial Infarction Complicated by Heart Failure, Left Ventricular Dysfunction, or Both
N. Engl. J. Med., November 13, 2003; 349(20): 1893 - 1906.
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