Veterbrates, and other higher life forms, circulate blood to maintain organ and tissue viability by transporting nutrients and removing wastes. A driving pressure exerted against vascular resistance governs blood flow. Blood pressure elevated above the mean for otherwise healthy people of equivalent age (hypertension) is noted in cardiovascular, cerebrovascular and renal disease in a complex chicken-egg relationship. In fact, otherwise well reasoned investigators expounded the view that a raised blood pressure was a compensatory "epi" phenomenon permitting the body to compensate for blood flow limited by vascular constriction. Until the end of World War II, there was no consensus among practitioners as to whether intervention to reduce hypertensive blood pressures was beneficial or indeed dangerous. It was the completion of large interventional, multicenter studies of the effect of blood pressure reduction on mortality in the 1960s that decisively answered the question of whether hypertension shortens life. It does!

Hypertension Increases the Risk of Death

Once the series of Veterans Administration hypertension trials unquestionably linked hypertension to a greater risk of death, multiple descendant issues of timing and type of appropriate therapy for hypertension became pressing.(1) Currently, medical expenditures for drugs to lower blood pressure amount to more than $30 billion(2) annually in the US despite that pragmatic reality that most of the 20% of Americans who are hypertensive(3) are treated inappropriately or inadequately.(4) Defining hypertension as either a systolic blood pressure >140 mm Hg or a diastolic blood pressure >90 mm Hg, more than 50 million people in the US, about one in four adults, are afflicted with hypertension.(5) With increasing age, the majority of those now living will become hypertensive: about 44% of individuals aged 50 to 59 years and 67% of those older than 70 years are hypertensive.(6)

Recognizing that the proportion of elderly Americans over the age of 65 will rise from 13% in 2000 to 15% by 2015, it is evident that the prevalence of hypertension will rise substantially.

As stated by Black,(7) of the one million annual deaths attributed to cardiovascular disease (50% coronary heart disease, 16% stroke, 4% heart failure), "Hypertension is an important antecedent for all these events, and high blood pressure alone is responsible for 40,000 of these deaths." There is a direct association between the level of hypertensive blood pressures and the risk of stroke.(8),(9) While the proof of causation between hypertension and end-stage renal disease is subject to dispute, there is no doubt that uncontrolled hypertension accelerates the loss of remaining renal function in those afflicted with essential hypertension(10) and diabetes.(11)

Contemporary Medical Antihypertensive Regimens Are Applied Ineffectively

Given the availability of potent antihypertensive drugs, it might be presumed that hypertension was well controlled - at least in the industrialized world. In fact, only about 27% of hypertensive Americans between the ages of 18 and 74 achieve blood pressure reduction of a level of <140/<90 mm Hg.(12) In other Westernized nations, the record is worse -- with a control rate of <6% in the United Kingdom(13) and 15% to 24% elsewhere (Figure 1).(14),(15)

Figure 1. Blood Pressure Control - International Comparisons.

Black HR Am J Hypertens. 1999; 12:113S-120S.

The "French "Paradox"(16) underscores the appropriateness of caution in linking hypertension alone or even as a key determinant of cardiovascular mortality. By all international comparisons, cardiovascular mortality is exceptionally low in France despite suboptimal control of blood pressure and dietary habits that include high content of animal fats and regular (daily) ingestion of wine.(17)

That hypertension can be proficiently treated as well by community physicians as by specialists in internal medicine was well demonstrated in the Hypertension Detection and Follow-up Program (HDFP), conducted from 1972 to 1979, in which 10,940 hypertensive adults were treated to a target diastolic blood pressure of <90 mm Hg for an entry level >100 mm Hg and to a targeted reduction of 10 mm Hg if the entry level was 90-99 mm Hg.(18) Over half of the treated patients reached their targeted blood pressure with resulting significant reduction in their 5-year mortality rates. Other confirmatory studies showed both that blood pressure can be lowered in large population cohorts and that, as a consequence, death rates will fall. No investigation better illustrated the adverse impact of hypertension on survival than the Framingham study that showed a continuous relationship between blood pressure and coronary events.(19)

Programs that Lower Hypertensive Blood Pressure Benefit the Majority of Those Enrolled

Because of the suggestion that aggressive lowering of diastolic blood pressure actually increased cardiovascular risk,(20) a huge Hypertension Optimal Treatment (HOT) study involving 18,700 patients was initiated.(21) A remarkable 92% of treated subjects actually reduced their diastolic blood pressure to <90 mm Hg while 57% evinced a diastolic blood pressure of <80 mm Hg, demonstrating the potential of community wide strategies for limiting the toll of hypertension. There was no increased risk of cardiovascular disease detected in the HOT study. Treated patients reported enhanced well being and fewer headaches. 

The Treatment of Mild Hypertension Study (TOMHS), in which five antihyypertensive drugs and a placebo were given along with lifestyle intervention,(22) confirmed the hypothesis that lowering hypertensive blood pressures enhances quality of life. Reduction of systolic blood pressure to <120 mm Hg permitted greater improvement in life quality than did an attained systolic blood pressure >120 mm Hg.

The very large (40,000 subjects) Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack (ALLHAT) study was designed to assess whether the attack rate for myocardial infarction was most favorably influenced by combining a diuretic with a choice among a calcium antagonist, an angiotensin converting enzyme inhibitor, or an a-adrenergic blocker.(23) By one year, 53% of those enrolled had blood pressures <140/<90 mm Hg, while by three years, 60% reached the targeted pressure reduction. Similarly, the Controlled Onset Verapamil Investigation of Cardiovascular Endpoints (CONVINCE) trial in 15,000 subjects, more than 60% of those enrolled had lowered their blood pressure to <140/<90 mm Hg by two years.(24)

At odds with the encouraging outcomes in organized, prospective clinical trials, such as those cited above, the usual outcome of hypertensive treatment noted in routine clinical practice is that of marginal benefit to outright failure. For example, a retrospective chart review of 500 veterans at five institutions by Berlowitz et al. found mean systolic blood pressure was unchanged over two years, while only 25% of subjects reached a blood pressure goal of <140/<90 mm Hg.(25)

Why physicians are not more vigorous in striving for blood pressure reduction in their hypertensive patients is subject to speculation with little insight. Perhaps the lack of short-term strict correlation between hypertension and its complications, as well as the exceptions to the rule, such as the low cardiovascular death rate in France despite persistent hypertension and dietary indiscretion (by American standards), are contributing factors.

High Risk Hypertensive Populations Unquestionably Benefitted by Blood Pressure Reduction

Three hypertensive subpopulations are at particular risk of developing both cardiovascular disease and worsening renal disease: those with diabetes, individuals with established renal disease and the elderly.(26) Reexamining the course of blood pressure in 2035 subjects in the Framingham Heart Study, Franklin et al. discerned a significant continuing linear increase in systolic blood pressure from age 30 through age 84(27) - a clearly identified risk factor for cardiovascular catastrophe.(28) Even modest reductions in systolic blood pressure in elderly patients consistently, in multiple trials, decrease the risk of stroke by 25-45% and congestive heart failure by 17-38%. The argument that blood pressure reduction is renoprotective in diabetic individuals with or without azotemia,(29) with or without proteinuria(30) and with or without microalbuminuria(31) is unassailable. Similarly, a mounting mass of evidence supports blood pressure reduction, especially with angiotensin converting enzyme inhibition, in those with proteinuria and renal disease.(32),(33),(34)

Which Drugs are Best for Hypertension?

Practitioners are perplexed by competing claims for one or another antihypertensive drugs in a continuously increasing menu of bewildering choices and drug categories, each proffering a selection of manipulated molecules. Does matching of drugs to disease or patient make a difference? When suffering through this challenging question, it is comforting to realize that Parving's singularly important study that opened the field of blood pressure reduction to preserve renal function was performed with now "primitive" drugs and without calcium channel blockers, angioitensin converting enzyme inhibitors or AT₁ receptor blockers.(35) In this simple yet perfect 39-month trial in ten type 1 diabetic adults, treatment with metoprolol, hydralazine and furosemide or thiazide: reduced blood pressure from 144/97 mm Hg to 128/84 mm Hg, reduced urinary albumin excretion from 977 micrograms/min to 433 micrograms/min and slowed decline in glomerular filtration rate from 0.91 ml/min/month to 0.39 ml/min/month. No subsequent study has achieved better results, though multiple confirmations over the past twenty years sustain the claim that lowering blood pressure not only protects against further kidney damage but may improve ongoing renal integrity in terms of filtration and protein leakage.

The dilemma of antihypertensive drug selection from the array of angiotensin converting enzyme inhibitors, calcium antagonists, angiotensin II receptor blockers, beta blockers and low-dose diuretics, alone or in combination, has no present solution. Because of the combined cardioprotective and renoprotective actions of angiotensin converting enzyme inhibitors, this class of antihypertensive is a good first choice - in increasing dosage to the maximum permitted (40 mg/day in the case of enalapril). Where the response is insufficient or side effects force withdrawal (cough, worsening azotemia, hyperkalemia), the second choice is a calcium blocker in sustained release form

Whether a beta blocker or diuretic is next added is an individualized decision. Even though weight reduction in those who are hypertensive and obese and dietary limitation of excessive salt intake are advocated adjunctive measures in any regimen for hypertension, they are of limited utility over the long-term. It is the physician's conviction that blood pressure reduction is advisable, coupled with persistence in encouraging patients through side effects and lagging compliance that makes the difference between treatment success and failure. There is no doubt that for the majority, antihypertesive therapy can be accomplished with reduction in mortality and protection of the heart and kidneys.

Take Home Message

Physicians, in the past, were reluctant to adopt broadly proven concepts such as the protective value of antisepsis and the hazard of cigarette smoking. At the start of our fresh millennium, the medical profession world-wide has not applied antihypertensive therapy to more than one-half of antihypertensive people, so that fewer than 30% have reduction in blood pressure to the consensus level of <140/<90 mm Hg. Even when constraints of drug cost are muted (Veterans Clinics), vigorous pursuit of normotension is the exception rather than the rule. By affirming the obvious, it is hoped that heightened awareness and treatment of a prevalent disorder may result.