Treatment to Prevent Cardiovascular Events
Studies Justifying the Use of Treatment to Prevent Cardiovascular Events
We are now in the era of “evidence-based medicine.” Although expert opinion and the results of nonrandomized trials and observational studies may provide guidance for us to make therapeutic decisions, it is generally agreed that the most reliable evidence is that obtained from large, prospective, well-controlled long-term clinical trials designed to evaluate clinical outcomes, not simply intermediate or surrogate end points. Fortunately, for those of us treating hypertension, such data are available and have been for decades.
Table Trials Addressing Whether Treating Diastolic Hypertension in Younger Persons Reduces Morbidity and Mortality
| Study | Date published |
| Veterans Administration Cooperative Study | 1967, 1970 |
| United States Public Health Services Study (USPHS) | 1977 |
| Australian Therapeutic Trials in Mild Hypertension | 1982 |
| Medical Research Council Trial (Medical Research Council) | 1985 |
Numerous clinical trials have been done to evaluate the value of treating hypertension. Some of the published trials have addressed whether patients with high blood pressure should be treated, some have looked at how aggressively they should be treated, and others have asked what classes of drug or drugs we should use to treat our hypertensive patients. Are there really important differences between classes of antihypertensives or is the only important thing that blood pressure be lowered? Finally, many clinical trials in hypertension are in progress. It is hoped that these studies will answer the many remaining questions. Pathophysiologic constructs are interesting but can be misleading. Epidemiologic analyses provide hypotheses for us to test. Only clinical trials done in people can confidently guide our treatment decisions and tell us how best to treat our patients.
Whether to treat younger persons with diastolic hypertension
Table Trials Addressing Whether Treating Diastolic Hypertension in Younger Persons Reduces Morbidity and Mortality lists the important trials that addressed the most basic question: Will reducing blood pressure also reduce morbidity and mortality in hypertensives? The first of these trials, the Veterans Administration Cooperative Study (VA) trial, began in 1964. By 1967 in only 143 subjects and after only 18 mo of follow-up, this study showed a clear benefit of active treatment for those with diastolic blood pressure between 115 and 129 mmHg. Treatment with a combination of a diuretic, vasodilator, and sympatholytic (reserpine) dramatically reduced hypertension-related mortal and morbid events (27 vs 2, respectively) compared to treatment with a placebo. In 1970, after an average of approx 3.3 yr of observation, the VA study also demonstrated the benefit of treating hypertensive patients with an entry diastolic blood pressure of 90-114 mmHg. Most of this benefit was evident in those with a diastolic blood pressure between 105 and 114 mmHg and in those with a comorbid condition and/or end organ damage, namely those with the highest absolute risk.
Over the next 15 yr, several other studies confirmed and extended those findings. These included the United States Public Health Service Study and the Australian Therapeutic Trial in Mild Hypertension. In both, diuretics were the initial active therapy. In the Medical Research Council trial, which enrolled 17,354 participants with a diastolic blood pressure between 95 and 109 mmHg, half of the volunteers were randomized to receive placebo and half to active therapy, of which 50% got a diuretic and 50% a β-blocker as initial treatment. These studies, together with the VA trial, clearly showed that treating diastolic hypertension reduces strokes by approx 40%, but neither individually nor in the aggregate could they show a statistically significant reduction in myocardial infarction or coronary artery disease events.
Whether to treat older persons with hypertension
What our goal should be for antihypertensive therapy
Which drugs or drug regimen to use to treat hypertension
Which drugs to use
What clinical trials currently in progress will tell us
More than 30 large randomized clinical trials in hypertension are currently in progress. The largest (42,500 have been recruited), the Antihypertensive Lipid Lowering Trial to Prevent Heart Attack (ALLHAT), is comparing an angiotensin-converting enzyme inhibitor, an a-blocker, and a dihydropyridine calcium antagonist to a diuretic in hypertensive patients over age 55 who have another cardiovascular risk factor or target organ damage. Myocardial infarction is the primary end point. This study, which has more than 15,000 type 2 diabetics, will tell us whether any of these classes of agents should be preferentially used in that subgroup. The Controlled Onset Cardiovascular Verapamil Trial of Cardiovascular Endpoints will compare older drugs (diuretics and β-blockers) to a nondihydropyridine calcium antagonist (verapamil as Covera HS), a preparation designed to be released in a similar fashion to the chronobiology of blood pressure and heart rate.
A number of studies will look at hypertensive diabetes with proteinuria, other studies will enroll hypertensive patients with life ventricular hypertrophy, and some studies are assessing the value of combined antihypertensive and lipid lowering therapy (ALLHAT and others) and/ or other therapies (folic acid and vitamin E) to prevent cardiovascular events in hypertensives. Finally, a study is currently being planned to determine whether treating older hypertensive patients with stage 1 systolic hypertension (systolic blood pressure 140-159/<90 mmHg) will reduce morbidity and mortality as was proven for stage 2 to 3 isolated systolic hypertension (>160 mmHg/<90 mmHg), in SHEP and SystEur.
Conclusion
In the more than three decades since the completion of the first clinical trial in hypertension, the VA trial, the value of treating hypertension is now solidly based on hard and unassailable evidence. Although these trials may not truly mimic what the practitioner deals with on a daily basis, practitioners treating patients with high blood pressure can be reasonably certain that much of what they are doing is evidence based, if they apply the lessons we have learned from clinical trials:
1. Rely on lifestyle modification to lower blood pressure modestly and make hypertension patients more responsive to treatment but not necessarily to prevent morbidity and mortality.
2. Begin treatment in hypertensive adults under the age of 60 with diuretics or β-blockers unless they have a comorbid condition or another clinical feature, which alters that choice.
3. Begin treatment in older hypertensive patients with either diuretics or a dihydropyridine calcium antagonist, especially if they have stage 2 to 3 isolated systolic hypertension.
4. Plan to treat to a diastolic blood pressure of <85 mmHg and even lower (<80 mmHg) in diabetics. The goal for systolic blood pressure is probably <140 mmHg in nondiabetics and <130 mmHg in diabetics.
5. Plan to need more than one drug for the majority of hypertensive patients and inform them that this may be the case.
6. Keep informed of the results of the many trials in progress and be willing to change practice if the data are compelling. If they are not, stay with what is known to be effective.
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