Prospective Randomized Amlodipine Survival Evaluation Research Articles

Liberation From the P Value's Tyranny.

> P-values, next to nuclear weapons, are the worst invention of the 20th century . > > —Herman Rubin, Purdue University, 1981 More than a half century ago, the P value was selected as the measuring tool for health care research by administrators. The difficulties generated by statistical hypothesis testing in addition to the constraints it places on cardiovascular trial researchers must now be declared unacceptable by the cardiology research community. Developed >90 years ago by statistician, Ronald Fisher, while working on a manure experiment in England,1,2 P values have risen to dominate the field of cardiovascular investigation for no other reasons than those of custom and habit. The abuse of P values has become so rampant that the American Statistical Association in 2016 was compelled to provide a consensus statement decrying their misuse.3 Counterpoint, see p 1049 Statistical hypothesis testing and P values were criticized by scientists from the beginning. They thought that its reverse logic—embracing a null hypothesis that one did not think, only to have the data reject it compelling the scientist to accept what one did think—was tortured and unnecessarily complex. P values rose to prominence in health care when grant administrators, journal editors, and Food and Drug Administration officials, overwhelmed by the post–World War II explosion in research, chose the P value instrument to help identify worthy research.4 The P value was not chosen because it had any basis in epidemiology, biology, pathophysiology, or cardiovascular medicine. It was selected because these administrators needed a metric to help them to separate the research wheat from the chaff, and they could see no alternative. The fledgling clinical trial research community accepted this P value imprimatur, not realizing that this nonmalicious selection portended pernicious consequences. Even though the P value’s sole, small role was to …

ST2 and Patient Prognosis in Chronic Heart Failure

Biomarkers of cardiovascular diseases are indispensable tools for diagnosis and prognosis, and the use of several biomarkers is now considered the standard of care.New markers continue to be developed, but few prove to be substantially better thanestablished markers. Suppression of tumorigenicity 2 (ST2) is a marker of cardiomyocyte stress and fibrosis that provides incremental value to natriuretic peptides for risk stratification of patients with a wide spectrum of cardiovascular diseases. On the basis of all available data, the 2013 American College of Cardiology and American Heart Association guidelines now recommend measurement of ST2 for additive risk stratification in patients with acute or chronic ambulatory heart failure (HF). This report provides an up-to-date overview of the clinical studies that led to the endorsement of ST2 as a cardiovascular prognostic marker in chronic HF. The presented data suggest that the addition of ST2 to a model that includes established mortality risk factors, including natriuretic peptides, substantially improves the risk stratification for death and HF hospitalization in patients with HF. ST2's prognostic value remains strong even in the subset of patients with renal insufficiency and is superior to other remodeling-fibrosis biomarkers currently being evaluated. In conclusion, these results have been repeatedly validated; thus, ST2 could be rapidly incorporated into clinical practice for risk prediction. Indeed, the body of evidence supporting the use of ST2 in chronic HF stratification continues to grow, with consistent data from cohorts around the world in single-center (Barcelona, Brussels, and San Diego cohorts) and multicenter (Penn Heart Failure Study [PHFS] and Muerte Subita en Insuficiencia Cardiac [MUSIC]) studies and in post hoc studies from clinical trials (Prospective Randomized Amlodipine Survival Evaluation 2 [PRAISE-2], Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training [HF-ACTION], and Controlled Rosuvastatin Multinational Trial in Heart Failure [CORONA]).

Is amlodipine more cardioprotective than other antihypertensive drug classes?

Is amlodipine more cardioprotective than other antihypertensive drug classes?

Association Between Bilirubin and Mode of Death in Severe Systolic Heart Failure

The bilirubin level has been associated with worse outcomes, but it has not been studied as a predictor for the mode of death in patients with systolic heart failure. The Prospective Randomized Amlodipine Evaluation Study (PRAISE) cohort (including New York Heart Association class IIIB-IV patients with left ventricular ejection fraction <30%, n = 1,135) was analyzed, divided by bilirubin level: ≤0.6 mg/dl, group 1; >0.6 to 1.2 mg/dl, group 2; and >1.2 mg/dl, group 3. Multivariate Cox proportional hazards models were used to determine the association of bilirubin with the risk of sudden or pump failure death. Total bilirubin was entered as a base 2 log-transformed variable (log2 bilirubin), indicating doubling of the bilirubin level corresponding to each increase in variable value. The higher bilirubin groups had a lower ejection fraction (range 19% to 21%), sodium (range 138 to 139 mmol/L), and systolic blood pressure (range 111 to 120 mm Hg), a greater heart rate (range 79 to 81 beats/min), and greater diuretic dosages (range 86 to 110 furosemide-equivalent total daily dose in mg). The overall survival rates declined with increasing bilirubin (24.3, 31.3, and 44.3 deaths per 100 person-years, respectively, for groups 1, 2, and 3). Although a positive relation was seen between log2 bilirubin and both pump failure risk and sudden death risk, the relation in multivariate modeling was significant only for pump failure mortality (hazard ratio 1.47, 95% confidence interval 1.19 to 1.82, p = 0.0004), not for sudden death mortality (hazard ratio 1.21, 95% confidence interval 0.98 to 1.49, p = 0.08). In conclusion, an increasing bilirubin level was significantly associated with the risk of pump failure death but not for sudden death in patients with severe systolic heart failure.

Uric acid level and allopurinol use as risk markers of mortality and morbidity in systolic heart failure

Previous studies have not extensively examined the association of hyperuricemia and adverse outcomes in systolic heart failure (HF) in relation to xanthine oxidase inhibitor therapy. The Prospective Randomized Amlodipine Survival Evaluation study included New York Heart Association class IIIB or IV patients with left ventricular ejection fraction <30%. For analysis, the population was divided into uric acid quartiles among nonallopurinol users (2.2-7.1, >7.1-8.6, >8.6-10.4, >10.4 mg/dL) and those using allopurinol. Multivariate Cox regression modeling was performed to identify predictors of mortality. Uric acid quartile and allopurinol groups were referenced to the lowest uric acid quartile. A total of 1,152 patients were included. In general, patients in the allopurinol group and in the highest uric acid quartile had indicators of more severe HF, including worse renal function and greater proportion of New York Heart Association class IV patients, and greater diuretic use. The allopurinol group and highest uric acid quartile had the highest total mortality (41.7 and 42.4 per 100 person-years, respectively) and combined morbidity/mortality (45.6 and 51.0 per 100 person-years, respectively). Allopurinol use and highest uric acid quartile were independently associated with mortality (hazard ratio [HR] 1.65, 95% CI 1.22-2.23, P = .001 and HR 1.35, 95% CI 1.07-1.72, P = .01, respectively) and combined morbidity/mortality (uric acid quartile 4 vs 1: HR 1.32, 95% CI 1.06-1.66, P = .02; allopurinol use: HR 1.48, 95% CI 1.11-1.99, P = .008). Elevated uric acid level was independently associated with mortality in patients with severe systolic HF, even when accounting for allopurinol use.

Associations of Gender and Etiology With Outcomes in Heart Failure With Systolic Dysfunction: A Pooled Analysis of 5 Randomized Control Trials

This study sought to explore the gender-related differences in etiology and outcomes in chronic heart failure (HF) patients from 5 randomized trials. Each year, 550,000 new cases of HF are identified; however, there remain limited data on gender-related differences in etiology and outcomes among patients with HF with systolic dysfunction. We analyzed data from 8,791 men and 2,851 women randomized in 5 clinical trials (PRAISE [Prospective Randomized Amlodipine Survival Evaluation], PRAISE-2, MERIT-HF [Metoprolol Extended Release Randomized Intervention Trial in Heart Failure], VEST [Vesnarinone Trial], and PROMISE [Prospective Randomized Milrinone Survival Evaluation]) to explore gender-related differences in etiology (ischemic vs. nonischemic) and outcomes (all-cause mortality and death or all-cause hospitalization). Hazard ratios (HR), 95% confidence intervals (CIs), and Kaplan-Meier survival curves were generated by gender and etiology. A total of 18% of ischemic and 31% of nonischemic patients were women. Irrespective of etiology, women were older, more ethnically diverse, and had higher systolic blood pressures, more diabetes, and severe HF symptoms, but less often smoked or had prior myocardial infarctions than men. Mean ejection fractions were similar between women (23.6%) and men (23.2%). The 1-year Kaplan-Meier survival estimates varied by gender and etiology (female nonischemics, HR 0.88 [95% CI 0.85 to 0.89]; female ischemics, HR 0.83 [95% CI 0.81 to 0.85]; male nonischemics, HR 0.84 [95% CI 0.83 to 0.85]; male ischemics, HR 0.79 [95% CI 0.78 to 0.81]). After adjustment, female gender (HR 0.77 [95% CI 0.69 to 0.85]) and nonischemic etiology (HR 0.80 [95% CI 0.72 to 0.89]) were associated with longer survival time. Time to death or hospitalization was longer among nonischemics (HR 0.83 [95% CI 0.78 to 0.89], p < 0.0001); however, female gender was not significantly associated with the composite outcome (HR 1.01 [95% CI 0.95 to 1.08]). Our data clarify that outcomes differ by both gender and etiology among patients with HF with systolic dysfunction. Understanding these differences may lead to better management of HF patients and improved overall prognosis.

Section 13: Evaluation and Therapy for Heart Failure in the Setting of Ischemic Heart Disease

Section 13: Evaluation and Therapy for Heart Failure in the Setting of Ischemic Heart Disease

Section 14: Managing Patients With Hypertension and Heart Failure

Section 14: Managing Patients With Hypertension and Heart Failure

Statin therapy is associated with lower mortality among patients with severe heart failure

Experimental considerations suggest both potential harm and benefit from statin therapy in patients with severe heart failure. However, relations of statin therapy with clinical outcomes in severe heart failure are not well established. Using data from the Prospective Randomized Amlodipine Survival Evaluation (PRAISE) trial, we evaluated associations of statin therapy with total mortality among 1,153 patients with severe heart failure (ejection fraction <30% and New York Heart Association class IIIB or IV symptoms) of ischemic and nonischemic etiologies. Statin therapy was administered to 134 patients (12%) during the study period. Over a 1.3-year mean follow-up, there were 413 deaths (29 deaths/100 person-years). Adjusting for age, gender, diabetes, smoking, heart failure etiology, ejection fraction, and New York Heart Association class, statin therapy was associated with a 62% lower risk of death (hazard ratio 0.38, 95% confidence interval 0.23 to 0.65), or 1 fewer death/5 patients taking statin therapy for 1 year. This association was not greatly altered by additional adjustment for a variety of other patient characteristics, including serum cholesterol levels. After propensity score analyses, statin therapy was still associated with a 48% lower risk of death (hazard ratio 0.52, 95% confidence interval 0.30 to 0.89). Although this observational study does not prove causality, further investigation of potential benefits of statins in patients with severe heart failure appears warranted.

Importance of echocardiography in patients with severe nonischemic heart failure: the second prospective randomized amlodipine survival evaluation (PRAISE-2) echocardiographic study

BackgroundEchocardiography is used commonly in clinical practice when caring for patients with heart failure. It is unknown whether the presence of certain findings provides an incremental ability to predict survival beyond the use of baseline clinical findings alone. The second PRAISE-2 echocardiographic study was prospectively designed to identify echocardiographic predictors of survival among patients with nonischemic cardiomyopathy and heart failure and to determine if components of the echocardiographic examination add prognostic information to baseline demographic and clinical information. MethodsOne hundred patients participated in the second Prospective Randomized Amlodipine Survival Evaluation Study (PRAISE-2) echocardiographic study; of these, 93 had full and interpretable echocardiographic examinations. Cox proportional hazards modeling was used to assess the relation between various characteristics and survival as well as to assess the incremental prognostic information gained by echocardiography beyond the clinical examination. ResultsSeven of 10 routine echocardiographic measures were significantly associated with death. These included mitral regurgitation (hazard ratio [HR], 2.31; 95% CI, 1.02, 5.27), left ventricular ejection fraction <20% (HR, 2.59; 95% CI, 1.14, 5.88), restrictive left ventricular filling pattern (HR, 2.37; 95% CI, 1.05, 5.32), and peak D velocity (HR, 1.62; 95% CI, 0.38, 0.87). The only statistically significant clinical predictor of survival was dyspnea at rest. The addition any of several echocardiographic parameters to baseline clinical information significantly improved the ability to predict survival. ConclusionsSeveral readily available echocardiographic parameters are predictive of death and when added to clinical examination findings significantly improve the ability to determine prognosis among patients with nonischemic cardiomyopathy and heart failure.

Neurohormones and oxidative stress in nonischemic cardiomyopathy: relationship to survival and the effect of treatment with amlodipine

Objectives The purpose of this study was to assess the effects of amlodipine on neurohormones and oxidative stress in nonischemic cardiomyopathy, and determine the relationship between baseline and posttreatment levels of these markers with survival. Background Neurohormones and oxidative stress are important in the pathophysiology of heart failure. Calcium-channel blockers are associated with poor outcomes in patients with heart failure, in part due to neurohormonal activation. In contrast, amlodipine, a second-generation dihydropyridine, has a more favorable clinical profile. Methods In the Prospective Randomized Amlodipine Survival Evaluation 2 (PRAISE-2) trial, a subset of 181 patients with nonischemic cardiomyopathy were randomized to amlodipine (10 mg/day) or placebo. Blood samples were evaluated at baseline, 2 weeks and 26 weeks for norepinephrine, epinephrine, angiotensin II, dopamine, N-terminal pro-atrial natriuretic peptide (Nt-pro-ANP), brain natriuretic peptide (BNP), adrenolutin and malondialdehyde. Results There was no difference in levels of neurohormones or oxidative stress markers between the amlodipine and placebo groups at the different times. Both Nt-pro-ANP and BNP decreased at 2 weeks and at 26 weeks. Baseline Nt-pro-ANP correlated with survival in multivariate analysis ( P = .001). A strong relationship was found between a reduction in BNP at 26 weeks and survival, with a hazard ratio of 0.153 (95% CI 0.051–0.461, P = .017). No relationship was found between markers of oxidative stress and survival. Conclusions We conclude that amlodipine does not affect circulating neurohormones and oxidative stress markers in patients with nonischemic cardiomyopathy treated with angiotensin-converting enzyme inhibitors, digoxin and diuretics. In addition, low circulating Nt-pro-ANP and a reduction in BNP over time confers a good prognosis.

Monitoring mortality at interim analyses while testing a composite endpoint at the final analysis

Mortality is often used as the clinical endpoint in clinical trials for acute diseases and takes precedence over any other outcome. A composite outcome such as death plus disease occurrence (or recurrence) or death plus hospitalization may also be considered, sometimes even as the primary outcome due to practical sample size issues. That is, a composite endpoint should have a higher event rate and thus a smaller sample size than for mortality alone to reach the same power. Two different scenarios are considered: in Scenario 1, the composite outcome is the primary endpoint and the mortality outcome is secondary; in Scenario 2, the mortality outcome is the primary endpoint and the composite outcome is secondary. In either scenario, the trial will be stopped if the simple mortality outcome shows an adverse effect or a significant benefit at an interim analysis, while the composite outcome will be tested at the final analysis if the mortality outcomes fails to show significance. These scenarios are typical in many trials sponsored by industry for regulatory approval. We refer to them as a switching the primary endpoint process. Two switching-endpoint procedures are proposed to calculate the efficacy boundary for the composite test statistic at the final analysis. The Bonferroni method is used in Method 1. In Method 2, the calculation is based upon the joint distribution of the test statistics for the simple mortality and the composite outcomes. A completed clinical trial, prospective randomized amlodipine survival evaluation (PRAISE-1), is used to illustrate the two switching-endpoint procedures. A simulation study shows that the two switching-endpoint procedures allow a trial to be stopped early due to a clinically relevant benefit in the mortality while preserving the overall alpha level.

Diuretic resistance predicts mortality in patients with advanced heart failure

Background In patients with chronic heart failure (CHF), diuretic requirements increase as the disease progresses. Because diuretic resistance can be overcome with escalating doses, the evaluation of CHF severity and prognosis may be incomplete without considering the intensity of therapy. Methods The prognostic importance of diuretic resistance (as evidenced by a high-dose requirement) was retrospectively evaluated in 1153 patients with advanced CHF who were enrolled in the Prospective Randomized Amlodipine Survival Evaluation (PRAISE). The relation of loop diuretic and angiotensin-converting enzyme inhibitor doses (defined by their median values) and other baseline characteristics to total and cause-specific mortality was determined by proportion hazards regression. Results High diuretic doses were independently associated with mortality, sudden death, and pump failure death (adjusted hazard ratios [HRs] 1.37 [P =.004], 1.39 [P =.042], and 1.51 [P =.034], respectively). Use of metolazone was an independent predictor of total mortality (adjusted HR = 1.37, P =.016) but not of cause-specific mortality. Low angiotensin-converting enzyme inhibitor dose was an independent predictor of pump failure death (adjusted HR = 2.21, P =.0005). Unadjusted mortality risks of congestion and its treatment were additive and comparable to those of established risk factors. Conclusions The independent association of high diuretic doses with mortality suggests that diuretic resistance should be considered an indicator of prognosis in patients with chronic CHF. These retrospective observations do not establish harm or rule out a long-term benefit of diuretics in CHF, because selection bias may entirely explain the relation of prescribed therapy to death. (Am Heart J 2002;144:31-8.)

Evaluation and Treatment of Patients With Systemic Hypertension

A 65-year-old man presented for evaluation of high blood pressure found on screening at a local health fair. History and physical examination did not show any signs or symptoms suggestive of a secondary cause, nor was there evidence of target end-organ damage except for grade 1 Keith-Wagener-Barker retinopathy. The patient denied taking any prescription or over-the-counter medications. Hypertension is the most common disease-specific reason Americans visit a physician. Despite the risks associated with an elevated blood pressure (BP), there is still woefully low achievement of recommended BP goals. From 1991 to 1994, only 27.4% of hypertensive Americans aged 18 to 74 years had a BP <140/90 mm Hg, the current stated goal for most people with hypertension, and in those with diabetes, less than half that number (11%) were controlled to the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure VI (JNC VI) recommended goal of <130/85 mm Hg.1 The present update will provide an overview of the evaluation and management of essential hypertension and help to guide clinicians in developing a management plan for a patient like the one described above. Taking a proper BP is an important first step in the diagnosis of hypertension.2 Using the proper cuff size with patients resting quietly and comfortably (with back support if seated) for at least 5 minutes before measurement, 2 or more readings separated by 2 minutes should be taken and averaged. Initial elevated BP readings should be confirmed on at least 2 subsequent visits over a period of 1 week or more. A value that is consistently ≥140/90 mm Hg is diagnostic in healthy patients; a value >130/80 mm Hg should be used for those with diabetes or kidney disease and proteinuria. Initial evaluation of the hypertensive patient focuses on the presence …

Can physicians always explain the results of clinical trials? a case study of amlodipine in heart failure

A lthough much emphasis is currently placed on evidence-based medicine, most of the decisions made in clinical practice are not based on data derived from randomized clinical trials. Perhaps this is to be expected, because it is impossible to conduct a trial to test the validity of every possible option available to physicians in the management of patients. Many therapeutic choices are so compelling that a test would be unethical; others are so trivial that a test might not be worth the time or effort. Yet, we cannot escape the fact that physicians do not practice evidence-based medicine even when evidence is available from randomized clinical trials. To most physicians, knowing the right answer is only the first step in the process of adopting a new treatment. They will not use a drug simply because they have seen data that indicate that it works; they will use the drug only when they have been told how it works. Indeed, for some, identification of the probable mechanism of action is the only prerequisite for adopting a new treatment. Such physicians will use a drug simply because it should work, even if there is no evidence that it does. The search for mechanisms has, in fact, emerged as a national preoccupation in the medical community. On the one hand, we will prescribe drugs that make mechanistic sense even if they are harmful; simply look at the enthusiasm for positive inotropic drugs for the treatment of chronic heart failure. On the other hand, we will avoid drugs that conflict with any preexisting view we might have of a disease even when the data supporting their use are overwhelming; witness, for example, the reluctance of physicians to prescribe b-blockers for the treatment of heart failure. The search for mechanisms drives (and haunts) all physicians, including those in academic medicine (who pride themselves on being rational) and those in primary-care medicine (who pride themselves on being practical). When the results of a clinical trial conflict with a widely held mechanistic model, we doubt the evidence from the study. When the results from clinical trials become so pervasive that they can no longer be ignored, we create and embrace a new model and forget the details of the trials. In the end, only the model survives. This should not be surprising: physicians are just like everyone else—we love a good story. The story of this supplement begins in March 1995. The results of a large-scale clinical trial known as the Prospective Randomized Amlodipine Survival Evaluation (PRAISE) study had just been presented at the Annual Scientific Sessions of the American College of Cardiology. The trial had randomized 1,153 patients with severe heart failure due to ischemic and nonischemic cardiomyopathy to treatment with placebo or amlodipine—with the intention of evaluating the long-term effect of the drug on morbidity and From the Division of Circulatory Physiology, Columbia University College of Physicians and Surgeons, New York, New York, USA (MP); and the Division of Cardiology, University of Florida Health Sciences Center, Jacksonville, Florida, USA (ABM). Address for reprints: Milton Packer, MD, Division of Circulatory Physiology, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, New York 10032.

Hospital use and costs among patients with nonischemic cardiomyopathy in the first Prospective Randomized Amlodipine Survival Evaluation study

The incidence of hospitalizations, lengths of stay, and per-diem costs were determined for 421 patients (amlodipine, 209; placebo, 212) with nonischemic cardiomyopathy in the first Prospective Randomized Amlodipine Survival Evaluation (PRAISE) study to assess the impact of amlodipine on hospital use and to compare the costs of hospitalization with the cost of amlodipine treatment. Treatment with amlodipine versus placebo significantly delayed the mean (± SD) time to first hospitalization (447 ± 26 d vs 315 ± 18 d, respectively; P = 0.0139). Both treatment groups showed a similar number of hospital admissions per patient per year. The overall hospital length of stay was 1.17 days less per year with amlodipine than with placebo, at a cost of $1098 less per person per year although these differences were not statistically significant. Significantly fewer amlodipine patients were admitted for unexplained cardiac arrest (odds ratio, 0.235; P = 0.002) and ventricular arrhythmias (odds ratio, 0.497; P = 0.004). These findings are consistent with clinical reports from PRAISE of prolonged survival and a reduction in sudden cardiac death among patients with severe heart failure due to nonischemic heart disease. This analysis suggests that in patients with nonischemic cardiomyopathy, treatment with amlodipine can delay the time to hospitalization and may reduce the number of hospital admissions related to ventricular arrhythmias. The estimated reduction in hospital costs of $1098 per year would more than offset the amlodipine treatment cost of approximately $700 per year.

Hospital utilization and cost among patients with nonischemic heart failure in the first prospective randomized amlodipine survival evaluation study (praise)

Hospital utilization and cost among patients with nonischemic heart failure in the first prospective randomized amlodipine survival evaluation study (praise)

Role of Cytokines in the Mechanism of Action of Amlodipine: The PRAISE Heart Failure Trial

Objectives. We sought to determine whether the beneficial effects of amlodipine in heart failure may be mediated by a reduction in tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) levels. We postulated that TNF-alpha and IL-6 levels may also have predictive value in patients with congestive heart failure (CHF).Background. The molecular mechanism for progression of CHF may involve cytokine overexpression. The effect of amlodipine on cytokine levels in patients with CHF is unknown.Methods. In the Prospective Randomized Amlodipine Survival Evaluation (PRAISE) trial, we used enzyme-linked immunosorbent assay to measure plasma levels of TNF-alpha in 92 patients and IL-6 in 62 patients in New York Heart Association functional classes III and IV randomized to receive amlodipine (10 mg/day) or placebo. Blood samples were obtained for cytokine measurement at baseline and at 8 and 26 weeks after enrollment.Results. The baseline amlodipine and placebo groups did not differ in demographics and cytokine levels. Mean (±SD) plasma levels of TNF-alpha were 5.69 ± 0.32 pg/ml, and those of IL-6 were 9.23 ± 1.26 pg/ml at baseline. These levels were elevated 6 and 10 times, respectively, compared with those of normal subjects (p < 0.001). Levels of TNF-alpha did not change significantly over the 26-week period (p = 0.69). However, IL-6 levels were significantly lower at 26 weeks in patients treated with amlodipine versus placebo (p = 0.007 by the Wilcoxon signed-rank test). An adverse event—CHF or death—occurred more commonly in patients with higher IL-6 levels.Conclusions. Amlodipine lowers plasma IL-6 levels in patients with CHF. The beneficial effect of amlodipine in CHF may be due to a reduction of cytokines such as IL-6.(J Am Coll Cardiol 1997;30:35–41)

Effect of amlodipine on morbidity and mortality in severe chronic heart failure: Milton Packer, Christopher M. O'Connor, Jalal K. Ghali, Milton L Pressler, Peter E. Carson, Robert N. Belkin, Alan B. Miller, Gerald W. Neuberg, David Frid, John H. Wertheimer, Anne B. Cropp, David L DeMets, for the Prospective Randomized Amlodipine Survival Evaluation Study Group. Division of Circulatory Physiology, Columbia

Effect of amlodipine on morbidity and mortality in severe chronic heart failure: Milton Packer, Christopher M. O'Connor, Jalal K. Ghali, Milton L Pressler, Peter E. Carson, Robert N. Belkin, Alan B. Miller, Gerald W. Neuberg, David Frid, John H. Wertheimer, Anne B. Cropp, David L DeMets, for the Prospective Randomized Amlodipine Survival Evaluation Study Group. Division of Circulatory Physiology, Columbia

What, if anything, is controversial about calcium antagonists?

Recent publications purporting to show that calcium antagonists, when used for the treatment of hypertension or in the post myocardial infarction patient, would paradoxically increase the rate of heart attack and mortality have cast doubts on the safety and efficacy of this drug class. All three studies are retrospective, and have various drawbacks. Specifically, the metaanalysis of Furberg et al is fraught with mistakes, of borderline significance, and based on old data pertaining to short-acting nifedipine only (which should not be given in patients who have suffered an acute heart attack). The case control study of Psaty et al suggested that hypertensive patients who were treated with short-acting verapamil, diltiazem, and nifedipine had an excessive rate of myocardial infarction when compared with patients who were treated with diuretics. Two out of the three calcium antagonists that were used in this study were not approved for the treatment of hypertension by the US Food and Drug Administration. Some patients were taking these drugs only once a day whereas, because of their short duration of action, at least a three or four times daily regimen would be required to achieve an acceptable blood pressure control throughout a 24-h period. The cohort study of Pahor et al suggested distinct differences among various calcium antagonists with regard to survival. Blood pressure was controlled in <40% of all patients, and in some patients blood pressure was never even measured. Recent studies, such as the Prospective Randomized Amlodipine Survival Evaluation (PRAISE), the third Vasolidator-Heart Failure Trial (VHeFT-III), the second Doppler Flow and Echocardiography in Functional Cardiac Insufficiency Assessment of Nisoldipine Therapy (DEFIANT II), the Angina Prognosis Study in Stockholm (APSIS), and the Shanghai Trial of Nifedipine in the Elderly (STONE), attest to the safety and efficacy of the newer long-acting calcium antagonists in patients with a wide spectrum of heart disease. Several ongoing trials including the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) with amlodipine, the International Nifedipine-GITS Study: Intervention as a Goal in Hypertension Treatment (INSIGHT) with nifedipine, the Hypertension. Optimal Treatment study (HOT) with felodipine, the Systolic Hypertension in the Elderly in Europe Trial (SYST-EUR) with nicardipine, the Second Swedish Trial in Old Patients with Hypertension (STOP II) with felodipine, and Nordic Diltiazem Study (NORDIL) with diltiazem, will give us morbidity and mortality data in patients with high blood pressure within the next few years. Until these results are available, we can be confident that the lowering of blood pressure and providing relief of patients with symptomatic angina can be achieved safely and efficiently with the presently available long-acting calcium antagonists.