IMPORTANT UNRESOLVED ISSUES
In Management of Hypertension

 Author:                         Hussien H. Rizk, MD    

Author Affiliation:         Cairo University. Faculty of Medicine. Cairo, Egypt.

Address:                      25, Abdel halim Hussien street, Cairo 12311 Egypt

E-mail:                                     hussienrizk@hotmail.com

The science of hypertension witnessed an explosive expansion of available data based on randomized clinical trials that involved huge numbers of patients, including most of the important subgroups of interest (elderly, women, diabetic, black, hypertensive patients with renal, cardiac, or cerebral disease, and dyslipidemic hypertensives). There appears to be a plethora of data comparing different individual antihypertensive drugs, different systolic and diastolic blood pressure targets, and different drug combinations, as well as trials of adjuvant therapy to reduce cardiovascular risk besides blood pressure reduction (aspirin, lipid lowering therapy, tight diabetes control, and anti-oxidants).

However, despite the availability and clarity of data, two important phenomena still plague the field, and continue to limit our ability to give our patients the full benefit of the currently available knowledge:

1- A continuing raging – largely commercially driven – debate about the best group of antihypertensive drugs to use for initiation of therapy

2- A huge gap between the numbers of hypertensive patients, and those who are aware of their disease, receive treatment, and have their blood pressure adequately controlled.

The following discussion seeks to find a way out of this deadlock, in order for the medical profession to realize the full benefit of medical knowledge for patient care.

I. Target Organ Protection. Are There True differences between Antihypertensive Drugs?

The magnitude of the hypertension epidemic is enormous. The life time probability of developing hypertension among middle-aged Framingham participants is 90% (1). The continued introduction and approval of new antihypertensive agents, in addition to important influences of the drug industry and the media, together with the rather frequent adverse effects of larger doses of beta adrenergic blockers and thiazide diuretics, have all contributed to igniting the debate about differences between antihypertensive drugs other than their blood pressure lowering efficacy.

Previous trials of hypertension treatment consistently documented that diuretic-based regimens substantially reduce the risk of stroke (2). However, the value of diuretics in coronary heart disease prevention was less than expected (3).

When the case-control study of Psaty et al (4) provided strong evidence that some calcium channel blockers increased the risk of myocardial infarction when used to treat hypertension, the potential risk of certain drugs caused more concern. Several trials compared the impact of different classes of antihypertensive agents on a wide range of clinical outcomes (including blood pressure control, adverse effects, cardiovascular events and total mortality) in a wide range of patients (including mild hypertension, elderly subjects, diabetic patients and hypertensive patients with target organ damage). However, most drug-drug comparisons were industry-sponsored and the majority compared only two drugs.

The accumulating data from this array of trials, and the way these data were used to promote new pharmaceutical products, constituted a background noise against which clinical wisdome needed to be exercised in order to reach to a prudent clinical decision in a myriad of misleading signals. Two facts, however became clear during this era:

First:  tight blood pressure control to <140/90 produced the best clinical outcome. Lower blood pressure targets in diabetes (<130/85) reduced the risk of major cardiovascular events compared to the less stringent target of <140/90 mmHg (5).

Second: there is a clear difference in the ability of ACE-inhibitors to reduce major cardiovascular events and total mortality between primary and secondary prevention situations. In a cohort without clinically manifest atherosclerotic disease or diabetes, ACE-inhibitors are not superior to diuretic-based regimens (6,7). On the other hand, studies of ACE-inhibitors in patients with myocardial infarction, heart failure (8), renal impairment (9) peripheral vascular disease, stroke or diabetes (10) who are largely normotensive revealed that - compared to placebo or other drug classes - these agents significantly reduce heart attack, heart failure, stroke, renal failure, and total mortality.

The results of ACE-inhibitor secondary prevention trials in largely normotensive patient populations were inappropriately extrapolated and commonly used to imply probable benefit of these agents in the prevention of cardiovascular events in hypertensive patients without clinically evident atherosclerotic disease. The effects of this trend in data mishandling on the cost of care of hypertensive patients were substantial.

The recently published “Antihypertensive and Lipid Lowering Treatment to prevent Heart Attack (ALLHAT) (7) contributes to settle the heated debate about the differential benefits of antihypertensive agents in reducing cardiovascular events and total mortality. This randomized double blind active-controlled trial recruited over 40,000 hypertensive patients > 55 years of age with at least one other cardiovascular disease risk factor (including smoking and diabetes). Patients were randomized to chlorthalidone, lisiropril, amlodipin or doxazosin. The doxazosin limb was prematurely discontinued due to increased risk of cardiovascular events and heart failure compared to the thiazide limb (11).

The mean age of ALLHAT participants was 67 years, the mean body mass index was 30. The population included 47% women, 35% black and 36% diabetic. The mean follow-up was about 5 years. The primary outcome of fatal and non-fatal coronary heart disease did not differ between groups on thiazide, amlodipine and lisinopril. However lisinopril significantly increased the risk of stroke and heart failure and amlodipin increased the risk of heart failure (both compared to cholorthalidone). In this study, the most effective drug was- luckily- the least expensive. Among pre-specified groups defined by age, sex, race and diabetes, the results were remarkably consistent. The results of ALLHAT are robust, unambiguous, and generalizable (12).

Clinicians have remain acutely aware of the basic fact that hypertensive patients die because of poor blood pressure control, and not because they are treated with drug A rather than drug B. Also, investigators have to resist the urge to continue comparing antihypertensive agents. Instead, doctors have to focus on getting their job done (13). The target is clear: hypertension control, and prevention of hypertension (14) in the first place.

II. The Gap between Knowing and Doing. Why hypertension is still poorly controlled?

In spite of the relative ease with which hypertension is diagnosed, and the abundance of effective medications with few adverse effects, the gross majority of hypertensive patients are either not diagnosed, not treated, or not controlled. The best hypertension control rate worldwide did not reach 30%, and the lowest rates of control are well below 10% (15).

There is clearly a wide gap between our knowledge as a medical community of hypertension diagnosis, treatment, and complications on one hand, and our effort and enthusiasm to detect, treat and monitor high blood pressure on the other hand. What are the causes of this gap? And why is it so stubborn?

Compliance may be defined as “the extent to which a person's behaviour coincides with the health care provider’s advice” (16). Compliance can be assessed in several ways. The punctuality with which the patient keeps appointment is an indicator of compliance. Although only a small percentage of patients in clinical trials drop out or withdraw (17), under everyday practice circumstances, much more patients drop out (18). The simplest way to evaluate compliance is to interview the patient about habits in taking the prescribed treatment. It is very helpful when the patient admits the non-compliant behaviour. However, in clinical trials there is only a poor relation between the rate of blood pressure normalization and the reported degree of compliance (19). Pill count has been the traditional way to monitor compliance in clinical trials (20). The value of this method in practice is questioned. Other methods- like monitoring prescription refill and electronic medication monitoring- are not practical in most parts of the Third World (which has very low rates of hypertension control).

The process of hypertension therapy (both by drugs and by life style modification) passes through three well-defined steps (21); adoption, execution and discontinuation.

Adoption: the patient has first to go through the difficult step of accepting the diagnosis of hypertension and its implications regarding the need for life style change and drug therapy, at a time when no symptoms are present, and no cardiovascular complications are evident. The input of the physician is of paramount and importance at this stage, particularly in explaining the contribution of blood pressure level and other risk factors to future complications, and the need for life-long intervention to control body weight, salt intake and other behaviours. The need for and expected adverse effect from drugs have to be discussed prior to prescribing a drug regimen.

Execution: this is the most difficult step for the patient. To help patients persist on taking medication regularly, doctors have to explain clearly and frequently the need for treatment, explain that they have the time and will to work with the patient, and recruit the efforts of the nurse and- if possible- the pharmacist to monitor and insure compliance with both drug treatment and follow-up visits (22). An open and confident doctor-patient relationship helps to recognize the patient’s barriers. Some interventions are known to improve patient’s compliance. These include educational material, self-monitoring of blood pressure, and telephone follow-up. Some known barriers to long-term adherence to the prescribed regimen are poor communication (from the doctor), low motivation (of the doctor, the patient, or both), logistical barriers (e.g. excessive medication cost), adverse effects, complex and ineffective regimens, frequent change of doctors and long time between follow-up visits (23). Patients frequently forget what they were told during the consultation (24).

Discontinuation: a substantial fraction of patients stop their treatment, usually with dropping out of follow-up. The responsibility for this behaviour is shared by doctors and patients. Doctors must recognize that defective compliance is the norm. They should not be disappointed if patients do not take medication as prescribed. It is only through this acceptance that they can resume an open discussion with patients to recognize barriers to compliance and try to work them out.

A structured questionnaire was used to test the knowledge and attitudes of a random sample of 198 primary care physicians and 1940 hypertensive patients in Egypt (Ibrahim and Saber unpublished data). Medication cost was chosen by 71% of physicians as the cause of poor compliance, while only 7% of the patients surveyed stated that cost was the reason for changing antihypertensive therapy. This marked discrepancy reflects poor communication and calls for serious work to build a more open doctor-patient relationship.

Meanwhile, doctors can follow a simple scheme to improve the compliance of their patients to the prescribed regimen:

1.       Make a complete diagnosis of hypertension and risk status.

2.       Explain it to the patient and make sure that he/she understands what you say.

3.       Stress that treatment is life long.

4.       Give due consideration to cost while prescribing.

5.       Prescribe simple, once-daily regimens.

6.       Allow and encourage extra visits for blood pressure measurement at no extra charge to the patient.

7.       Arrange follow-up visits no more than two months apart during the first year.

8.       Ask the patient to write down the date he/she opened each new box of pills, and count the remaining pills at each visit.

9.       Encourage home blood pressure measurement.

10.   Consider that poor compliance is the rule, do not be upset, and work harder.

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