A Review of Perindopril in the Reduction of Cardiovascular Events

Duncan J CampbellSt. Vincent’s Institute of Medical Research and the Department of Medicine, University of Melbourne, St. Vincent’s Hospital, Fitzroy, Victoria, AustraliaBackground: Angiotensin-converting enzyme inhibitors (ACEI) have a well-established role in the prevention of cardiovascular events in hypertension, left ventricular dysfunction, and heart failure. More recently, ACEI have been shown to prevent cardiovascular events in individuals with increased cardiovascular risk, where hypertension, left ventricular dysfunction, or heart failure was not the primary indication for ACEI therapy.Objective: To review studies of the effects of the ACEI perindopril on cardiovascular events.Method: The EUROPA (European Trial on Reduction of Cardiac Events with Perindopril in Patients with Stable Coronary Artery Disease Study), PROGRESS (Perindopril Protection Against Recurrent Stroke Study), and ASCOT-BPLA (Anglo-Scandinavian Cardiac Outcomes Trial – Blood Pressure Lowering Arm) trials are reviewed.Results: Perindopril alone reduced cardiovascular events in subjects with stable coronary heart disease. Perindopril in combination with indapamide reduced cardiovascular events in subjects with cerebrovascular disease. Perindopril in combination with amlodipine reduced cardiovascular events in subjects with hypertension.Conclusion: Perindopril reduced cardiovascular events. The reduction of cardiovascular events by perindopril was in large part associated with reduction of blood pressure, and greater reduction in cardiovascular events was associated with greater reduction of blood pressure. Perindopril may need to be combined with other antihypertensive agents to maximize reduction of cardiovascular events.Keywords: Angiotensin-converting enzyme inhibitor, hypertension, coronary heart disease, stroke, myocardial infarction, heart failur

Is blood pressure reduction a valid surrogate endpoint for stroke prevention? an analysis incorporating a systematic review of randomised controlled trials, a by-trial weighted errors-in-variables regression, the surrogate threshold effect (STE) and the biomarker-surrogacy (BioSurrogate) evaluation schema (BSES)

<p>Abstract</p> <p>Background</p> <p>Blood pressure is considered to be a leading example of a valid surrogate endpoint. The aims of this study were to (i) formally evaluate systolic and diastolic blood pressure reduction as a surrogate endpoint for stroke prevention and (ii) determine what blood pressure reduction would predict a stroke benefit.</p> <p>Methods</p> <p>We identified randomised trials of at least six months duration comparing any pharmacologic anti-hypertensive treatment to placebo or no treatment, and reporting baseline blood pressure, on-trial blood pressure, and fatal and non-fatal stroke. Trials with fewer than five strokes in at least one arm were excluded. Errors-in-variables weighted least squares regression modelled the reduction in stroke as a function of systolic blood pressure reduction and diastolic blood pressure reduction respectively. The lower 95% prediction band was used to determine the minimum systolic blood pressure and diastolic blood pressure difference, the surrogate threshold effect (STE), below which there would be no predicted stroke benefit. The STE was used to generate the surrogate threshold effect proportion (STEP), a surrogacy metric, which with the R-squared trial-level association was used to evaluate blood pressure as a surrogate endpoint for stroke using the Biomarker-Surrogacy Evaluation Schema (BSES3).</p> <p>Results</p> <p>In 18 qualifying trials representing all pharmacologic drug classes of antihypertensives, assuming a reliability coefficient of 0.9, the surrogate threshold effect for a stroke benefit was 7.1 mmHg for systolic blood pressure and 2.4 mmHg for diastolic blood pressure. The trial-level association was 0.41 and 0.64 and the STEP was 66% and 78% for systolic and diastolic blood pressure respectively. The STE and STEP were more robust to measurement error in the independent variable than R-squared trial-level associations. Using the BSES3, assuming a reliability coefficient of 0.9, systolic blood pressure was a B + grade and diastolic blood pressure was an A grade surrogate endpoint for stroke prevention. In comparison, using the same stroke data sets, no STEs could be estimated for cardiovascular (CV) mortality or all-cause mortality reduction, although the STE for CV mortality approached 25 mmHg for systolic blood pressure.</p> <p>Conclusions</p> <p>In this report we provide the first surrogate threshold effect (STE) values for systolic and diastolic blood pressure. We suggest the STEs have face and content validity, evidenced by the inclusivity of trial populations, subject populations and pharmacologic intervention populations in their calculation. We propose that the STE and STEP metrics offer another method of evaluating the evidence supporting surrogate endpoints. We demonstrate how surrogacy evaluations are strengthened if formally evaluated within specific-context evaluation frameworks using the Biomarker- Surrogate Evaluation Schema (BSES3), and we discuss the implications of our evaluation of blood pressure on other biomarkers and patient-reported instruments in relation to surrogacy metrics and trial design.</p

Beyond the Evidence of the New Hypertension Guidelines. Blood pressure measurement – is it good enough for accurate diagnosis of hypertension? Time might be in, for a paradigm shift (I)

Despite widespread availability of a large body of evidence in the area of hypertension, the translation of that evidence into viable recommendations aimed at improving the quality of health care is very difficult, sometimes to the point of questionable acceptability and overall credibility of the guidelines advocating those recommendations. The scientific community world-wide and especially professionals interested in the topic of hypertension are witnessing currently an unprecedented debate over the issue of appropriateness of using different drugs/drug classes for the treatment of hypertension. An endless supply of recent and less recent "drug-news", some in support of, others against the current guidelines, justifying the use of selected types of drug treatment or criticising other, are coming out in the scientific literature on an almost weekly basis. The latest of such debate (at the time of writing this paper) pertains the safety profile of ARBs vs ACE inhibitors. To great extent, the factual situation has been fuelled by the new hypertension guidelines (different for USA, Europe, New Zeeland and UK) through, apparently small inconsistencies and conflicting messages, that might have generated substantial and perpetuating confusion among both prescribing physicians and their patients, regardless of their country of origin. The overwhelming message conveyed by most guidelines and opinion leaders is the widespread use of diuretics as first-line agents in all patients with blood pressure above a certain cut-off level and the increasingly aggressive approach towards diagnosis and treatment of hypertension. This, apparently well-justified, logical and easily comprehensible message is unfortunately miss-obeyed by most physicians, on both parts of the Atlantic. Amazingly, the message assumes a universal simplicity of both diagnosis and treatment of hypertension, while ignoring several hypertension-specific variables, commonly known to have high level of complexity, such as: - accuracy of recorded blood pressure and the great inter-observer variability, - diversity in the competency and training of diagnosing physician, - individual patient/disease profile with highly subjective preferences, - difficulty in reaching consensus among opinion leaders, - pharmaceutical industry's influence, and, nonetheless, - the large variability in the efficacy and safety of the antihypertensive drugs. The present 2-series article attempts to identify and review possible causes that might have, at least in part, generated the current healthcare anachronism (I); to highlight the current trend to account for the uncertainties related to the fixed blood pressure cut-off point and the possible solutions to improve accuracy of diagnosis and treatment of hypertension (II)

Testing devices for the prevention and treatment of stroke and its complications

We are entering a challenging but exciting period when many new interventions may appear for stroke based on the use of devices. Hopefully these will lead to improved outcomes at a cost that can be afforded in most parts of the world. Nevertheless, it is vital that lessons are learnt from failures in the development of pharmacological interventions (and from some early device studies), including inadequate preclinical testing, suboptimal trial design and analysis, and underpowered studies. The device industry is far more disparate than that seen for pharmaceuticals; companies are very variable in size and experience in stroke, and are developing interventions across a wide range of stroke treatment and prevention. It is vital that companies work together where sales and marketing are not involved, including in understanding basic stroke mechanisms, prospective systematic reviews, and education of physicians. Where possible, industry and academics should also work closely together to ensure trials are designed to be relevant to patient care and outcomes. Additionally, regulation of the device industry lags behind that for pharmaceuticals, and it is critical that new interventions are shown to be safe and effective rather than just feasible. Phase IV postmarketing surveillance studies will also be needed to ensure that devices are safe when used in the ‘real-world’ and to pick up uncommon adverse events