Heart Outcomes Prevention Evaluation Trial Research Articles

Lowering Nighttime Blood Pressure With Bedtime Dosing of Antihypertensive Medications: Controversies in Hypertension - Con Side of the Argument.

Lowering Nighttime Blood Pressure With Bedtime Dosing of Antihypertensive Medications: Controversies in Hypertension - Con Side of the Argument.

Clinical trials of intensive versus less intensive control of hypertension: HOPE or HYPE?

The recently published Heart Outcomes Prevention Evaluation trial (HOPE-3) demonstrated no benefit of lowering blood pressure with candesartan and hydrochlorothiazide in persons at intermediate cardiovascular risk and with adequate blood pressure control as determined by the enrolling physician. The results of Systolic Blood Pressure Intervention Trial (SPRINT) and HOPE-3 highlight the importance of considering differences in study design and patient population when interpreting the results of clinical trials.

The Prognostic Significance of Bundle Branch Block in High‐Risk Chronic Stable Vascular Disease Patients: A Report from the HOPE Trial

The prognostic significance of left and right bundle branch block (LBBB and RRBB) in patients with chronic stable cardiovascular (CV) disease is not well characterized and was evaluated in the Heart Outcomes Prevention Evaluation (HOPE) study cohort. Observational analysis of data prospectively collected in the HOPE trial. HOPE was a multicenter, international trial, which evaluated ramipril and vitamin E in 9,541 patients aged > or = 55 years with CV disease or diabetes with > or = 1 CV risk factor(s) but without heart failure (HF) or known left ventricular systolic dysfunction. Follow-up extended for a median of 4.5 years. Electrocardiograms were obtained at baseline in all study participants and were read centrally. Major CV events (defined as CV death, myocardial infarction, or stroke), heart failure, CV death, all-cause death, and sudden death. Baseline LBBB was present in 246 (2.6%) patients and was associated with increased risk for major CV events (HR = 1.54; 95% CI, 1.18-2.02), CV death (HR 2.29; 95% CI, 1.63-3.20), heart failure (HR 2.99; 95% CI, 2.31-3.87), sudden death (HR 3.17; 95% CI, 2.13-4.73), and all-cause death (HR = 2.10; 95% CI, 1.59-2.77). In multivariate models, LBBB remained an independent predictor of heart failure, sudden death, CV death, and all-cause death (P < or = 0.002 for all). Baseline RBBB was present in 428 (4.5%) of patients and was not associated with increased CV risk. In patients with stable chronic CV disease, LBBB but not RBBB is an independent predictor of heart failure, sudden death, CV death, and all-cause death.

When the Clinical Trials Raise More Questions Than Answers: Blood Pressure Controversy Beyond the TRANSCEND Results

Many trials have reported that in high-risk hypertensive patients, blood pressure (BP) control must be effectively achieved as soon as possible, following the motto ‘‘the lower and the sooner, the better.’’ Surprisingly, in the Telmisartan Randomized Assessment Study in ACEIntolerant Subjects With Cardiovascular Disease (TRANSCEND) where all of the patients were high-risk and more than 75% were hypertensive, a marked reduction in BP did not attain the expected results. This study included patients who were treated with an angiotensin receptor blocker and who were intolerant to angiotensinconverting enzyme (ACE) inhibitor therapy. Could this be due to BP-lowering benefits that will depend only on baseline values? Should we accept that BP reduction is just one goal, and not the most relevant, in high-risk hypertensive patients? Could there be a BP threshold beyond which further reduction will not be effective in improving outcomes? After TRANSCEND, the answers are more than ever ‘‘blowing in the wind.’’ It must be kept in mind that most of the population included in trials in which a significant improvement after intensive BP reduction has been demonstrated exhibited higher baseline BPs. These patients markedly benefit from an antihypertensive regimen. On the other hand, it had been assumed that the results of the Heart Outcomes Prevention Evaluation (HOPE) could be directly translated to the TRANSCEND population. However, patients included in these studies were significantly different. In the HOPE study, patients were less rigorously treated, with fewer antiplatelets, statins, and b-blockers used. What results would have been obtained with ramipril as part of a regimen as it was in the HOPE trial if tested on the TRANSCEND study population? It is likely that the benefits would have been less dramatic. Since the management of hypertensive patients has markedly improved in the past decades, the benefits provided by the addition of new drugs to regimens that include other antihypertension agents, statins, or aspirin, will be less promising in terms of morbidity and mortality reduction.

Treatment with angiotensin-converting enzyme inhibitors: insight into perindopril cardiovascular protection

Angiotensin-converting enzyme (ACE) inhibitors have an established role in the treatment of patients across the cardiovascular disease continuum, from uncomplicated hypertension to established cardiovascular disease. The first data showing the efficacy of ACE inhibitors for the prevention of cardiovascular events came from the Heart Outcomes Prevention Evaluation trial with ramipril. Since then a number of other large, randomized, controlled trials have confirmed the beneficial effects of ACE inhibitors on cardiovascular outcomes in a variety of patient groups. In addition, evidence suggests that these beneficial effects of ACE inhibitors occur independently of their blood pressure (BP)-lowering effects, a phenomenon that has not been observed for angiotensin receptor blockers. Among the ACE inhibitors, perindopril has the greatest body of evidence for cardiovascular preventive efficacy from major morbidity–mortality trials (e.g. ADVANCE, ASCOT-BPLA, EUROPA, PREAMI, PEP-CHF, PROGRESS). In addition, perindopril may be the treatment of choice in stable coronary artery disease because of its unique anti-apoptotic activity and protective effects on the endothelium. A current major trend in cardiovascular medicine is the increased use of combination therapies. The data reviewed here suggest that any combination therapy for secondary prevention across the continuum of cardiovascular disease should contain an ACE inhibitor.

Angiotensin Receptor Blockers and Cardiovascular Protection: Are We ONTARGET?

It is well known that activation of the renin-angiotensin system (RAS) plays a crucial role in the initiation and progression of cardiovascular disease (CVD) and target organ damage in patients with hypertension. There is growing recognition that RAS inhibition provides protection against cardiovascular damage, irrespective of blood pressure (BP) levels. Angiotensin-converting enzyme (ACE) inhibitors have been shown to prevent cardiovascular, neurologic, and renal complications in high-risk patients. With the realization that ACE inhibitors do not provide optimal blockade of the RAS, angiotensin receptor blockers (ARBs) have been developed. Although the efficacy of ARBs in the treatment of hypertension is comparable with that of ACE inhibitors, the former class of drugs has not yielded consistent or superior effects on target organ protection. Therefore, an unsettled issue in preventive medicine has been whether ARBs are as effective as (or superior to) ACE inhibitors in high-risk populations. The Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET), evaluating whether the ARB telmisartan is as least as effective as (noninferior to) the ACE inhibitor ramipril and whether the combination of the 2 drugs is superior to ramipril, was recently reported at the 2008 American College of Cardiology meeting and published. 1 Although ARBs have demonstrated efficacy in other cardiovascular and renal protection therapeutic trials, the clinical outcomes have been limited to special patient populations, such as patients with acute myocardial infarctions in the Valsartan in Acute Myocardial Infarction Trial (VALIANT) 2 and patients with heart failure in the Valsartan Heart Failure Trial (Val-HeFT) 3 and the Candesartan in Heart Failure—Assessment of Reduction in Mortality and Morbidity (CHARM) trial. 4 Therefore, the findings of these highly specialized research studies may not be applicable to the relatively large segment of asymptomatic patients who are at high risk for CVD. The significance of the ONTARGET trial is that it was conducted in a large high-risk patient population similar to most patients treated in community practice. The ONTARGET results establish that an ARB (telmisartan) is noninferior to and preserves cardioprotective effects compared with ramipril, the “gold standard” of ACE inhibitors, with much better overall tolerability. The study also confirms that ARBs offer significant vascular protection. As a result, blockade of the RAS with ARBs is now validated to be as effective as with ACE inhibitors for reducing cardiovascular risk in patients with multiple risk factors. Although not universally accepted, it has been widely postulated that the vascular protection offered by ACE inhibitors may be independent of BP. 5,6 The Heart Outcomes Prevention Evaluation (HOPE) trial 5 and the European Trial on Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease (EUROPA), 6 for example, showed that long-term therapy with ACE inhibitors (ramipril and perindopril, respectively) in high-risk patients who are not necessarily hypertensive provides vascular protection. The Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) trial 7 provided evidence in support of similar BP-independent results for the ARB losartan. In general, these results suggest that the cardiovascular protection conferred by the therapies was not necessarily or always based on reductions in BP. Recent studies suggest that RAS blockade may also reduce the incidence of cerebrovascular events in high-risk groups. The risk for stroke was reduced with ramipril in the HOPE trial. 5 Subsequently, the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) 8 showed that treatment

Prevention of cardiovascular events in end-stage renal disease: Results of a randomized trial of fosinopril and implications for future studies

Cardiovascular events (CVEs) are the leading cause of death in chronic hemodialysis patients. Results of trials in non-end-stage renal disease (ESRD) patients cannot be extrapolated to patients with ESRD. It is critical to test cardiovascular therapies in these high-risk patients who are usually excluded from major cardiovascular trials. The study objective was to evaluate the effect of fosinopril on CVEs in patients with ESRD. Eligible patients were randomized to fosinopril 5 mg titrated to 20 mg daily (n=196) or placebo (n=201) plus conventional therapy for 24 months. The primary end point was combined fatal and nonfatal first major CVEs (cardiovascular death, resuscitated death, nonfatal stroke, heart failure, myocardial infarction, or revascularization). No significant benefit for fosinopril was observed in the intent to treat analysis (n=397) after adjusting for independent predictors of CVEs (RR=0.93, 95% confidence interval (CI) 0.68-1.26, P=0.35). The per protocol secondary supportive analysis (n=380) found a trend towards benefit for fosinopril (adjusted RR=0.79 (95% CI 0.59-1.1, P=0.099)). In the patients who were hypertensive at baseline, systolic and diastolic blood pressures were significantly decreased in the fosinopril as compared to the placebo group. After adjustment for risk factors, trends were observed suggesting fosinopril may be associated with a lower risk of CVEs. These trends may have become statistically significant had the sample size been larger, and these findings warrant further study.

Are the Eutrophic Effects of Angiotensin Receptor Blockers Real?

HomeHypertensionVol. 48, No. 4Are the Eutrophic Effects of Angiotensin Receptor Blockers Real? Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBAre the Eutrophic Effects of Angiotensin Receptor Blockers Real? Flávio Danni. Fuchs Flávio Danni. FuchsFlávio Danni. Fuchs Division of Cardiology, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil Search for more papers by this author Originally published21 Aug 2006https://doi.org/10.1161/01.HYP.0000238605.34864.9fHypertension. 2006;48:E18Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: August 21, 2006: Previous Version 1 To the Editor:In a laborious experimental study, Savoia et al1 concluded that the addition of valsartan but not atenolol to the antihypertensive treatment decreased the resistance artery media/lumen ratio of diabetic patients. On the basis of such a finding, the authors suggest that it may be preferable to achieve tight blood pressure (BP) control by using angiotensin receptor blockers in addition to other antihypertensive agents to improve vascular structure and reduce cardiovascular risk in diabetic hypertensive patients. I do believe that this advantage was not clearly demonstrated in this study, and even if it was done, it could not be extended to other antihypertensive agents.The lower efficacy of atenolol in terms of prevention of cardiovascular events was demonstrated repeatedly in elderly patients.2 At least in this age group, atenolol should not be used anymore as first-line therapy or as a comparison drug in clinical trials.3 Probably most of the lower efficacy of atenolol in this setting is attributable to a lower BP-lowering effect in this age group, a phenomenon evident in the first 6 months of the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm trial.3 In the experiment of Savoia et al,1 patients were ≈60 years old, on the average, in the atenolol group. The authors assumed that BP did not vary between groups at the end of the experiment, but the data suggest the contrary. Systolic BP was 4.8 mm Hg lower in the valsartan group, and pulse pressure 2.4 mm Hg. The absence of formal statistical significance may be secondary to a β error, in view of the small sample size of the experiment. Moreover, similar office BP values may conceal substantial differences in BP along the 24-hour period, as was shown in the Heart Outcomes Prevention Evaluation trial.4My main point, however, is related to the statistical analysis of this experiment. The analysis based on the within-group statistics in experiments with 2 groups is questionable. The right approach seems to be to perform a between-group comparison of changes of variation in the media/lumen ratio or any other parameter or to use the significance of F value for the group/time interaction in repeated measurements and the multiple factors ANOVA procedure. In addition, the groups differed substantially in terms of potential confounding variables, such as age (patients in the atenolol group were 4.5 years older, on average), baseline diabetes control (worst in the valsartan group), and mainly BP at the end of and presumably during the experiment. An ANCOVA procedure for changes (after minus before values) of the media/lumen ratio controlling for confounding is required in this case to identify an independent drug effect. And finally, media thickness was unchanged in both groups after the experiment, showing that the effect, if any, was restricted to arteriolar lumen (again a trend, not statistically significant), in accordance with the between-group difference in BP.These shortcomings cast doubt on the internal validity of this experiment, which does not support the preference for any type of antihypertensive agent to reach tight BP control in patients with diabetes. The importance of the BP versus eutrophic effects of antagonists of the renin–angiotensin system is still an open issue and requires further clinical and experimental investigations.DisclosuresNone.1 Savoia C, Touyz RM, Endemann DH, Pu Q, Ko EA, De Ciuceis C, Schiffrin EL. Angiotensin receptor blocker added to previous antihypertensive agents on arteries of diabetic hypertensive patients. Hypertension. 2006; 48: 271–277.LinkGoogle Scholar2 Carlberg B, Samuelsson O, Lindholm LH. Atenolol in hypertension: is it a wise choice? Lancet. 2004; 364: 1684–1689.CrossrefMedlineGoogle Scholar3 Fuchs FD, Gus M, Ribeiro JP. ASCOT-BPLA [letter]. Lancet. 2006; 367: 205.CrossrefGoogle Scholar4 Svensson P, Faire U, Sleight P, Yusuf S, Östergren J. Comparative effects of ramipril on ambulatory and office blood pressures: A HOPE substudy. Hypertension. 2001; 38: e28–e32.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Fuchs F (2018) Prevention and Treatment Essentials of Hypertension, 10.1007/978-3-319-63272-8_4, (101-145), . Savoia C, Touyz R and Schiffrin E (2006) Response to Are the Eutrophic Effects of Angiotensin Receptor Blockers Real?, Hypertension, 48:4, (E19-E19), Online publication date: 1-Oct-2006. October 2006Vol 48, Issue 4 Advertisement Article InformationMetrics https://doi.org/10.1161/01.HYP.0000238605.34864.9fPMID: 16923991 Originally publishedAugust 21, 2006 PDF download Advertisement SubjectsACE/Angiotensin Receptors/Renin Angiotensin SystemRemodelingSmooth Muscle Proliferation and Differentiation

More Confusing Messages From the Hypertension Treatment Trials

More Confusing Messages From the Hypertension Treatment Trials

Patients undergoing coronary revascularisation: a missed opportunity for secondary prevention?

Background: This study tested the hypothesis that the opportunity to start secondary prevention therapy before discharge after coronary revascularisation is being missed. The study assessed current prescribing practice and identified...

Impact of cigarette smoking in high-risk patients participating in a clinical trial. A substudy from the Heart Outcomes Prevention Evaluation (HOPE) trial

In recent large cardiovascular trials done in stable patients, 14-31% of the participants were smokers; the consequences of smoking in these trials using medications known to reduce cardiovascular events, have not been assessed. We evaluated the cardiovascular outcomes according to smoking status of men and women participating in the Heart Outcomes Prevention Evaluation trial. The occurrence of cardiovascular events was documented among participants who did not change their smoking status during the trial. There were 2728 'never smokers', 5241 'former smokers' and 936 'current smokers', and all had stable cardiovascular disease or diabetes with at least one other risk factor. None had previous congestive heart failure or known left ventricular ejection fraction < 0.40. During the 4.5-year follow-up, there were 641 cardiovascular deaths, 978 myocardial infarctions, 358 strokes and 1021 deaths. In comparison to 'never smokers', smokers had relative risks adjusted for confounding variables including medications known to reduce cardiovascular mortality and morbidity, for cardiovascular death of 1.65 [95% confidence interval (CI), 1.28-2.14], for myocardial infarction of 1.26 (95% CI, 1.01-1.58), for stroke of 1.42 (95% CI, 1.00-2.04), and for total mortality of 1.99 (95% CI, 1.63-2.44). The rates of these events among 'former smokers' were not different from those of 'never smokers'. Smoking increased the risk of mortality and morbidity among high-risk patients despite the use of medications known to reduce cardiovascular events. Smoking cessation programs should be reinforced even for patients participating in clinical trials.

Impact of Cigarette Smoking in High-Risk Patients Participating in a Clinical Trial. A Substudy from the Heart Outcomes Prevention Evaluation (HOPE) Trial

Background In recent large cardiovascular trials done in stable patients, 14-31% of the participants were smokers; the consequences of smoking in these trials using medications known to reduce cardiovascular events, have not been assessed. Design We evaluated the cardiovascular outcomes according to smoking status of men and women participating in the Heart Outcomes Prevention Evaluation trial. Methods The occurrence of cardiovascular events was documented among participants who did not change their smoking status during the trial. There were 2728 ‘never smokers’, 5241 ‘former smokers’ and 936 ‘current smokers’, and all had stable cardiovascular disease or diabetes with at least one other risk factor. None had previous congestive heart failure or known left ventricular ejection fraction &lt; 0.40. Results During the 4.5-year follow-up, there were 641 cardiovascular deaths, 978 myocardial infarctions, 358 strokes and 1021 deaths. In comparison to ‘never smokers’, smokers had relative risks adjusted for confounding variables including medications known to reduce cardiovascular mortality and morbidity, for cardiovascular death of 1.65 [95% confidence interval (CI), 1.28-2.14], for myocardial infarction of 1.26 (95% CI, 1.01-1.58), for stroke of 1.42 (95% CI, 1.00-2.04), and for total mortality of 1.99 (95% CI, 1.63-2.44). The rates of these events among ‘former smokers’ were not different from those of ‘never smokers’. Conclusions Smoking increased the risk of mortality and morbidity among high-risk patients despite the use of medications known to reduce cardiovascular events. Smoking cessation programs should be reinforced even for patients participating in clinical trials.

Cost effectiveness of ramipril in patients at high risk for cardiovascular events : economic evaluation of the HOPE (Heart Outcomes Prevention Evaluation) study for Germany from the Statutory Health Insurance perspective.

In the HOPE (Heart Outcomes Prevention Evaluation) trial, ramipril (compared with placebo) significantly reduced cardiovascular death and all-cause mortality as well as the incidence of costly cardiovascular events, such as myocardial infarction, revascularisation, stroke, cardiac arrest, hospitalisation due to heart failure and worsening angina pectoris, new-onset diabetes mellitus and microvascular diabetic complications. Data from the HOPE study were used in a cost-effectiveness analysis to determine the additional cost per life-year gained (LYG) when the ACE inhibitor ramipril was added to the current medication of patients at high risk for cardiovascular events. The aim was to establish the incremental cost-effectiveness ratio (ICER) of ramipril versus placebo from the perspective of the Statutory Health Insurance (SHI) provider in Germany, for both the study population as a whole and for the subgroup of patients with diabetes. A modelling approach was used, based on secondary analysis of published data and retrospective application of costs. In the base-case analysis, average case-related expenses of the SHI were applied and LYG were quantified using the average of the difference between the survival rates in the ramipril and placebo groups during the HOPE trial. LYG beyond the trial duration were estimated by the method of declining exponential approximation of life expectancy. After a treatment period of 4.5 years, the ICER of ramipril versus placebo was Euros 4074/LYG and Euros 2486/LYG (discounted at 5% per annum and in 1998-2002 values; Euro 1 approximately USD 0.88; first quarter 2002 values) for the HOPE study population as a whole and the subgroup of patients with diabetes, respectively. To test the model's robustness, the influence of the model variables on the results was quantified using a deterministic model, and a best-case/worst-case scenario analysis. The effect of random variables was investigated in a Monte Carlo simulation. The acquisition cost for ramipril had the greatest impact on the ICER of ramipril (2.2-fold greater than the impact of the number of LYG). In 95% of the 10,000 simulation steps, the ICER of ramipril after 4.5 years of treatment was between Euros 1290 and Euros 9005 per LYG for the entire HOPE study population and between Euros 290 and Euros 6115 per LYG in the diabetic subgroup. Results of this evaluation suggest that ramipril is likely to be cost effective in secondary prevention of cardiovascular events from the perspective of the SHI (third-party payer) in Germany. The estimated ICER of ramipril compares well with other ICERs of widely accepted treatments used for the management of cardiovascular diseases, such as HMG-CoA reductase inhibitors.

Angiotensin-converting enzyme inhibitors and stroke risk: benefit beyond blood pressure reduction?

Hypertension, a leading cause of morbidity and mortality, accounts for 25-49% of all strokes. Randomized placebo-controlled trials primarily with diuretics and beta-blockers administered in patients with hypertension have demonstrated a 38% reduction in primary stroke. Placebo-controlled trials with angiotensin-converting enzyme (ACE) inhibitors have not been conducted in patients with hypertension. However, in a meta-analysis of four placebo-controlled trials of ACE inhibitors in patients with coronary heart disease and/or diabetes mellitus, the overall risk of primary stroke was significantly reduced. Results of the Heart Outcomes Prevention Evaluation trial, which produced a substantial reduction in stroke with an apparently small reduction in blood pressure, suggest that the benefit of ACE inhibitors may be related to their effects on the renin-angiotensin-aldosterone system more than on blood pressure reduction. In active-control comparisons in patients with hypertension, ACE inhibitors have demonstrated reductions in primary stroke risk similar to reductions with diuretics, beta-blockers, and calcium channel blockers. The data suggest that for primary prevention of stroke antihypertensive therapy should be individualized in patients. Relatively few data are available concerning the benefit of antihypertensive therapy in the secondary prevention of stroke. In patients who had experienced a stroke or transient ischemic attack, therapy with a diuretic or a combination of a diuretic plus an ACE inhibitor could be recommended based on available outcome studies conducted in this patient population. It is premature to conclude that the benefit of ACE inhibitor therapy in primary or secondary prevention of stroke is an effect independent of blood pressure reduction. Hypertension detection, treatment, and control in patients still must be the principal focus of clinicians for both primary and secondary prevention of stroke.

Analysis of Recent Papers in Hypertension

Analysis of Recent Papers in Hypertension

Prevention of Type 2 Diabetes Mellitus Through Inhibition of the Renin-Angiotensin System

Type 2 diabetes mellitus is becoming a major health problem associated with excess morbidity and mortality. As the prevalence of type 2 diabetes is rapidly increasing, prevention of the disease should be considered as a key objective in the near future. Besides lifestyle changes, various pharmacological treatments have proven their efficacy in placebo-controlled clinical trials, including antidiabetic drugs such as metformin, acarbose and troglitazone, or antiobesity agents such as orlistat. Arterial hypertension, a clinical entity in which insulin resistance is common, is strongly associated with type 2 diabetes and may precede the disease by several years. While antihypertensive agents such as diuretics or beta-adrenoceptor antagonists may worsen insulin resistance and impair glucose tolerance, newer antihypertensive agents exert neutral or even slightly positive metabolic effects. Numerous clinical trials have investigated the effects of ACE inhibitors or angiotensin II receptor antagonists (ARAs) on insulin sensitivity in hypertensive patients, with or without diabetes, with no consistent results. Almost half of the studies with ACE inhibitors in hypertensive nondiabetic individuals demonstrated a slight but significant increase in insulin sensitivity as assessed by insulin-stimulated glucose disposal during a euglycaemic hyperinsulinaemic clamp, while the other half failed to reveal any significant change. The effects of ARAs on insulin sensitivity are neutral in most studies. Mechanisms of improvement of glucose tolerance and insulin sensitivity through the inhibition of the renin-angiotensin system (RAS) are complex. They may include improvement of blood flow and microcirculation in skeletal muscles and, thereby, enhancement of insulin and glucose delivery to the insulin-sensitive tissues, facilitating insulin signalling at the cellular level and improvement of insulin secretion by the beta cells. Six recent large-scale clinical studies reported a remarkably consistent reduction in the incidence of type 2 diabetes in hypertensive patients treated with either ACE inhibitors or ARAs for 3-6 years, compared with a thiazide diuretic, beta-adrenoceptor antagonist, the calcium channel antagonist amlodipine or even placebo. The relative risk reduction averaged 14% (p = 0.034) in the CAPPP (Captopril Prevention Project) with captopril compared with a thiazide or beta1-adrenoceptor antagonist, 34% (p < 0.001) in the HOPE (Heart Outcomes Prevention Evaluation) study with ramipril compared with placebo, 30% (p < 0.001) in the ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) with lisinopril compared with chlortalidone, 25% (p < 0.001) in the LIFE (Losartan Intervention For Endpoint reduction in hypertension study) with losartan compared with atenolol, and 25% (p = 0.09) in the SCOPE (Study on Cognition and Prognosis in the Elderly) with candesartan cilexetil compared with placebo, and 23% (p < 0.0001) in the VALUE (Valsartan Antihypertensive Long-term Use Evaluation) trial with valsartan compared with amlodipine. All these studies considered the development of diabetes as a secondary endpoint, except the HOPE trial where it was a post hoc analysis. These encouraging observations led to the initiation of two large, prospective, placebo-controlled randomised clinical trials whose primary outcome is the prevention of type 2 diabetes: the DREAM (Diabetes REduction Approaches with ramipril and rosiglitazone Medications) trial with the ACE inhibitor ramipril and the NAVIGATOR (Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research) trial with the ARA valsartan. Finally, ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) will also investigate as a secondary endpoint whether it is possible to prevent the development of type 2 diabetes by blocking the RAS with either an ACE inhibitor or an ARA or a combination of both. Thus, the recent consistent observations of a 14-34% reduction of the development of diabetes in hypertensive patients receiving ACE inhibitors or ARAs are exciting. From a theoretical point of view, they emphasise that there are many aspects of the pathogenesis, prevention and treatment of type 2 diabetes that still need to be uncovered. From a practical point of view, they may offer a new strategy to reduce the ongoing epidemic and burden of type 2 diabetes.

Clinical pharmacy specialist implementation of lisinopril therapy in patients with coronary artery disease and diabetes mellitus.

As the results of the Heart Outcomes Prevention Evaluation trial suggested that patients with both coronary artery disease (CAD) and diabetes mellitus would benefit from angiotensin-converting enzyme (ACE) inhibitor therapy, our objective was to increase the percentage of patients with both of these conditions receiving the goal dosage (20 mg/day) or highest tolerated dosage of the ACE inhibitor lisinopril through intervention of a clinical pharmacy service. Prospective study with historic comparison (control group). Clinical Pharmacy Cardiac Risk Service. Hospitalized patients with CAD and type 2 diabetes mellitus. At hospital discharge, lisinopril 5 mg/day was started in eligible patients; the drug was titrated to a goal dosage of 20 mg/day or the highest tolerated dosage. Potassium level, serum creatinine level, and blood pressure were monitored at baseline, at each dosage titration, and 2 weeks after the goal or highest tolerated dosage was reached. The group receiving usual care (control group) consisted of 95 patients; the treatment group had 101 patients. At baseline, 19 patients (20%) in the control group were receiving the goal dosage of lisinopril, 34 (36%) were taking a suboptimal dosage, 16 (17%) were excluded from treatment, and 26 (27%) were eligible but were not receiving lisinopril therapy. After 9 months, ACE inhibitor dosages had changed minimally in the control group. In the treatment group, at baseline, 37 patients (36%) were at their goal dosage and therefore titration was not necessary; 15 (15%) were receiving a suboptimal dosage, 35 (35%) were excluded from treatment, and 14 (14%) were eligible but not receiving therapy. After the titration period, 55 (54%) treatment group patients were at the goal dosage, 11 (11%) were taking a suboptimal dosage, and 35 (35%) were not candidates for ACE inhibitor therapy. The most common reasons for exclusion were renal insufficiency, cough, and baseline hypotension. Changes in potassium level, serum creatinine level, and blood pressure were not significant during the study. The clinical pharmacy service more than doubled the number of patients with CAD and diabetes who achieved the goal dosage of an ACE inhibitor, a drug class that has been shown to decrease morbidity and mortality in this patient population.

Use of Angiotensin-Converting enzyme inhibitors after coronary artery bypass grafting in patients with diabetes mellitus

The Heart Outcomes Prevention Evaluation (HOPE) trial demonstrated a 22% relative reduction in cardiovascular events with ramipril therapy in patients with vascular disease.1 The Microalbuminuria, Cardiovascular and Renal Outcomes (MICRO-HOPE) trial (a substudy of the HOPE Trial) established that ramipril reduced cardiovascular events by 24% in 2,139 diabetic patients with known coronary artery disease (CAD) (32% of whom were recruited after coronary artery bypass grafting [CABG]), irrespective of comorbidities or concomitant medication use.2 Although the HOPE trial and the MICRO-HOPE substudy were published in major medical journals, widely publicized, and aggressively marketed, the medical literature is rife with examples where evidence is incompletely translated into practice. In particular, a recent study found that even the sites that took part in a clinical trial establishing the benefits of angiotensin-converting enzyme (ACE) inhibitors in acute myocardial infarction were no more likely to subsequently treat their infarction patients with ACE inhibitors than nontrial sites.3 As our hospital was 1 of the participating sites in HOPE/MICRO-HOPE, we decided to examine the use of ACE inhibitors in diabetic patients with advanced coronary artery disease who had undergone CABG after publication of the HOPE/MICRO-HOPE studies in January 2000.

HOPE study impact on ACE inhibitors use.

Angiotensin-converting enzyme (ACE) inhibitors are used to treat cardiovascular diseases, major causes of death in Canada. The HOPE (Heart Outcomes Prevention Evaluation) study showed that ramipril benefits patients at high risk for cardiovascular disease. We analyzed ACE inhibitor use and costs in Canada before and after publication of HOPE. We obtained pharmacy and hospital sales data for 1985-2001 from IMS Canada for all ACE inhibitors (Anatomical Therapeutic Category code C09A0) and for the 3 largest provinces (i.e., British Columbia, Quebec, Ontario). Prescription numbers, total costs, cost/prescription, and market share of individual ACE inhibitors were plotted over time and analyzed using regression. Canadian dollars were used to report costs. We examined 10 drugs; captopril was the first, introduced in 1985. Overall, prescriptions increased consistently from 356 000 in 1985 to 11.5 million in 2001, representing an annual increase of 660 000 (y = 661 410x-510 360; r(2) = 0.99). Total costs increased linearly from 1985 (14.5 million US dollars) to 2001 (513 million US dollars): Y = 29.3.10(6)x - 29.9.10(6); r(2) = 0.99. Provincial utilization patterns were also similar. Ramipril's national use increased dramatically from 1999 (822 000 prescriptions, 9.2% of all ACE inhibitors) to 2001 (3.8 million, 32.8% of all ACE inhibitors). National costs for ramipril increased exponentially (y = 1.08e(0.6248x)) to a total of 157 million US dollars in 2001, with the 3 major provinces accounting for 78.9%. Costs per prescription followed no observable trend (range 39.45-46.20 US dollars). The number of prescriptions and the total cost of ACE inhibitors increased over the period studied. Ramipril use increased in concert with publication of the HOPE trial, while the growth rates of other ACE inhibitors remained constant.

Ramipril for the prevention and treatment of cardiovascular disease.

To evaluate the effectiveness of ramipril in the prevention and treatment of cardiovascular disease and determine its need for inclusion on a formulary. A MEDLINE and PubMed database search was conducted (1987-May 2002). Only journals written in the English language were selected for review. DATA EXTRACTION AND STUDY SELECTION: Articles reporting the use of ramipril in humans were evaluated. Emphasis was placed on randomized, controlled trials assessing efficacy. Ramipril is an angiotensin-converting enzyme (ACE) inhibitor that exerts its effects through inhibition of the renin-angiotensin-aldosterone system. It exhibits a safety profile that is similar to that of other ACE inhibitors and is comparable in cost to the majority of the available agents. Clinical trials have proven the effectiveness of ACE inhibitors in the treatment of hypertension, heart failure, and nephropathy. Ramipril, however, is the only ACE inhibitor currently approved for the prevention of cardiovascular events in high-risk patients without evidence of left-ventricular dysfunction or heart failure, based on the results of the HOPE (Heart Outcomes Prevention Evaluation) trial. Whether this effect is specific to ramipril has yet to be proven. This article emphasizes the major trials involving ramipril including the AIRE (Acute Infarction Ramipril Efficacy), REIN (Ramipril Efficacy in Nephropathy), and HOPE trials. Although similar to other ACE inhibitors in many aspects, it cannot be assumed that the benefits shown with ramipril in the HOPE trial are a class effect. Ongoing trials should help to clarify this matter. Until this time, current evidence justifies the inclusion of ramipril on a formulary.