TRIAL DESIGN AND CONTROL OF ANTIHYPERTENSIVE IN CLINICAL RESEARCH

 

ABOUT AUTHOR:
Raj Kishor
Avigna Clinical Research Institute
Bangalore, India
raryan859@gmail.com

ABSTRACT
The pharmacologic treatment of hypertension (HT) has been extensively studied by clinical trials. These studies have provided definitive evidence of treatment benefit and the weight and consistency of the clinical evidence has lead to uniformity in many aspects of treatment recommendations worldwide. The international guidelines and current clinical and biostatistical practices were reviewed for relevant clinical, design, end-point assessments and regulatory issues. The results are grouped mainly into ethical, protocol and assessment issues. Ethical issues arise as placebo-controlled trials (PCTs) for HT-lowering agents in patients with moderate to severe HT are undertaken. Patients with organ damage due to HT should not be included in long-term PCT. Active-control trials, however, are suitable for all randomized subsets of patients, including men and women, and different ethnic and age groups. Severity subgroups must be studied separately with consideration to specific study design. Safety studies must be very vigilant on hypotension, orthostatic hypotension and effects on heart. In dose-response studies, at least three doses in addition to placebo should be used to well characterize the benefits and side-effects. Mortality and morbidity outcome studies are not required in anti-HT trials except when significant mortality and cardiovascular morbidity are suspected. Generally, changes in both systolic and diastolic blood pressures (BP) at the end of the dosing interval from the baseline are compared between the active and the control arms as the primary endpoint of anti-HT effect.


REFERENCE ID: PHARMATUTOR-ART-1859

INTRODUCTION
The world wide increment of hypertension (HT) and cardiovascular diseases (CVD) is becoming heavier than ever before with each passing year. It is estimated that by 2025, up to 1.58 billion adults worldwide will suffer from some complications of or from HT. [1] that makes one out of each three adults, on an average, will develop clinical HT or its co-morbidities or both. Currently, the prevalence of HT varies around the world, with the lowest prevalence in rural India (3.4% in men and 6.8% in women)[2] and the highest prevalence in Poland (68.9% in men and 72.5% in women).[2] However, in fact, the low-prevalence rates, e.g. as those cited for India, do not necessarily mean a really low occurrence of the disease in this population. Even in those who are diagnosed with HT, treatment is frequently inadequate. In any case, regardless of the prevalence rate, large or small, HT and related diseases must be intervened for prevention, diagnosis and control.There are numerous trials in hypertension many of which have focused on cardiovascular(CV) outcomes (death, non–fatal Myocardial Infarction, stroke, congestive heart failure).These trials have influenced our clinical practice in terms of setting out guidelines in the treatment of Hypertension.



EARLY AND CURRENT APPROACHES IN HT TRIALS

Early:


In the late 1960s to early 1970s the trials were carried out in rather select populations (both high- and low-risk elderly patients), and were mainly interested in efficacy measurement of the anti-HT drugs in lowering BP relative to placebo or no treatment. The trials of the 1980s focused on middle-aged hypertensive individuals and later on the elderly. These trials mainly investigated the efficacy of β-blockers and diuretics in reducing the systolic BP in these patients. These early efficacy trials did not address the effect of anti-HT agents in controlling serious co morbidities like MI, CHD and CHF. Their compliance with Good Clinical Practices (GCP) was also rather poor. [3]

Current:


During the 90s, large randomized trials in a much broader patient population came in vogue and a great portion of these trials elucidated whether and whom to treat with different classes of anti-HT drugs. Continuing to date, these trials of angiotensin converting enzyme inhibitors (ACEIs), β-blockers, angiotensin receptor blockers (ARBs) and calcium channel blockers (CCBs) investigated the exact end-point goals, such as reduction of a certain percent of risk of MIs in Grade II HT patients over 1 year of treatment. The trials evaluated, often, the superiority of the end-point reduction by one agent over another as opposed to the overall efficacy of one agent or the other. Reduction in the relative risk of mortality from the primary and secondary outcome measures is one of the main objectives of the RCTs over the last 5–7 years. [3, 4]The reason for the outcome measurement shifting from lowering of BP to other parameters is that for some drugs, the BP lowering is an inadequate marker (surrogate) of health benefits in HT. Anti-HT drugs can have other important actions that may alter the benefit of lowering of BP. For example, many anti-HT drugs have shown consistent beneficial effects on long-term mortality and morbidity, most clearly on stroke and less consistently on cardiovascular events, such as, low- and high-dose diuretics, reserpine and β-blockers, usually as part of combination therapy. [5]

PROTOCOL CONSIDERATIONS

The trial patient population:
For participation in RCTs for HT or its co morbidities, any patient with a BP >120/80 mmHg, especially with one additional risk factor such as body mass index >25, is at risk of developing clinical HT and may qualify for the trial. For example, BP values between 130 and 139/85 and 89 mmHg are associated with a more than two-fold increase in the relative risk from CVD as compared with those with a BP of 120/80 mmHg or below.[3] Patients who are of 55 years of age or more and are also obese or diabetic are particularly risk-prone.


Currently, the patient population studied with a new anti-HT includes a broad range of patients with HT and its co morbidities. For mild to moderate HT, however, only BP can be studied in a CT by measuring both DBP and SBP over the study period. More severe HT is usually studied with relevant concomitant illness, e.g. CHD and DM. Care should be taken that the drugs they need would not interfere with the observations of the effects of the study drug. For example, for patients with CHF, standard treatment requires use of one to several agents (ACE inhibitors) affecting BP, which could have pharmacological actions similar to those of the study drug.[5]

Grading of HT together with target organ damage (TOD) secondary to HT needs to be established accurately. Patients, e.g. with BP >160/110 mmHg and DM, cannot be included in PCTs. Such patients, however, can be included in active-controlled trials with proper safety monitoring. Patients from relevant demographic subsets should be studied, including both men and women, racial/ethnic groups pertinent to the region and both young and older patients. The very old or “fragile elderly,” i.e Patients >75 years old, should be included.

In general, all population subsets should be included in the same studies rather than conducting studies in subgroups. This facilitates comparisons across subsets in the same environment. An exception would be severity of the subgroups, where study designs could be different for different severities. Patients with secondary HT, isolated systolic HT, HT during pregnancy and children with HT should be studied separately if specific indications for use in those populations are being sought. [5]

RCT’S of antihypertensive agents:


All recent trials, since the 1990s, for the assessment of efficacy and safety of anti-HT drugs have been designed and conducted as randomized, blinded trials.[6] Such trials are not only free of experimental bias but they are also balanced in all important aspects of the study and differ only in the intervention that the experimental and the control groups receive. As discussed further in the following section, many big trials, such as INVEST (The International Verapamil –Trandolapril study hypertension) and ALLHAT(Antihypertensive and lipid lowering to prevent heart attack trial), are designed as prospective, randomized, open, blinded-end point evaluation (PROBE) investigations in thousands of patients in multiple countries. In some studies, there is also an emphasis on the determination of the reduction of mortality and/or CV morbidity by the experimental treatments rather than measuring just the BP-lowering effects.[7] Well-designed and well-conducted RCTs have been able to estimate such complex end-points with a great deal of success.

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