Early and Aggressive Treatment of Complex Hypertension

Cardiovascular disease (CVD) morbidity and mortality associated with hypertension (HTN) arises primarily as a direct consequence of uncontrolled or elevated blood pressure (BP) resulting in congestive heart failure, coronary artery disease, stroke, and chronic kidney disease. Diabetes mellitus type 2 (DM2), and its attendant complications are accelerated by the coexistence of HTN. ¹ The comorbid conditions of DM2 and HTN are associated with increased CVD, stroke, chronic kidney disease and retinopathy. ¹ , ² Complex HTN is a term used for those hypertensive patients with clinical evidence of target‐organ damage such as ischemic heart disease, stroke, and chronic kidney disease. It also applies to patients with conditions associated with HTN such as the cardiometabolic syndrome, DM2, and coronary artery disease. Finally, some other high‐risk populations such as the elderly and African Americans may be classified as having complex HTN. ³ Achieving BP goals in patients with complex HTN is challenging ⁴ ; furthermore, emerging evidence suggests that the current guidelines regarding when to start therapy and what goals to achieve may not be aggressive enough. ⁵ The Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) currently classifies HTN into three categories; Pre‐HTN (120–139/80–89 mm Hg), stage 1 HTN (140–159/90–99 mm Hg) and stage 2 HTN (≥160/≥100 mm Hg). BP <120 mm Hg systolic and 80 mm Hg diastolic are considered normal.

SHOULD WE BE REACHING LOWER BP TARGETS MORE RAPIDLY IN PATIENTS WITH COMPLEX HTN?

Results from several recent trials underscore the need for more aggressive treatment in patients with complex HTN. The Comparison of Amlodipine vs. Enalapril to Limit Occurrences of Thrombosis (CAMELOT) study ⁶ evaluated the effect of the antihypertensive medications amlodipine and enalapril on reduction of cardiovascular events and progression to atherosclerosis by intravascular ultrasound. Both amlodipine and enalapril showed a directionally similar effect on reduction of the composite end point of cardiovascular events, although the outcome was not statistically significant for enalapril. The end points included CVD death, nonfatal myocardial infarction, resuscitated cardiac arrest, coronary revascularization, and hospitalization for angina pectoris, congestive heart failure, and stroke. There was a continuous relationship between BP reduction and atherosclerosis progression, even within the range of BP that would be considered “normal.” Overall, a 5/3 mm Hg reduction in BP was associated with a 31% reduction in CVD events. The study included both men and women with a mean age of 30–79 years and mean baseline BP of 129/78 mm Hg. Angiotensin‐converting enzyme inhibitors, angiotensin receptor blockers, and calcium channel blockers were discontinued before the study. Forty percent of the study participants were not known to be hypertensive before the study. After randomization, the BP was rapidly titrated to a maximum tolerated dose within 1 month, and ultimate BP was attained within the first 6 months of therapy. Participants were matched for age, gender, lipid and BP control, antihypertensive medications, and body mass index. The benefit in reduction of cardiovascular events was achieved in conjunction with optimal lipid control and 95% use of aspirin. The most striking slowing of atherosclerosis progression was seen in patients with systolic BP greater than the mean, suggesting that CVD event reduction is related to both basal and treated BP, even within the “normal” ranges.

The recent International Verapamil SR‐Trandolapril Study ⁷ (INVEST) diabetes cohort study evaluated 6400 diabetics among the 22,756 hypertensive participants. ⁷ The study compared treatment with verapamil sustained‐release and atenolol in a prespecified analysis of diabetes patients. During 2.7 years of follow‐up, 913 diabetics suffered a primary outcome event. There was no significant difference in the two treatment strategies as far as cardiovascular outcome. In this study, previous CVD events such as baseline heart failure, renal impairment, previous stroke or myocardial infarction, or peripheral vascular disease predicted primary outcome. Baseline BP control was 151.1/85.5 mm Hg in the verapamil group and 150.5/85.4 mm Hg in the atenolol group. By the end of the study; more than 40% of patients were at the goal BP of 130/85 mm Hg, considerably better than the BP control rate in practice‐based settings ⁴ and other trials. ⁸ Of note, a decrease in primary outcome was evident in both treatment groups at BP ≤140/90 mm Hg and was directly related to decreased BP until a measurement of <110/60 mm Hg, beyond which risk appeared to increase. These results are similar to those of the Controlled Onset Verapamil Investigation of Cardiovascular Endpoints (CONVINCE) trial, ⁹ which showed that verapamil is at least as effective as atenolol or hydrochlorothiazide in reducing CVD outcome. Median follow up for both studies was 2.7 and 3 years, respectively, and attainment of BP goals occurred in the first 6 months of therapy. Collectively, these data suggest that early initiation of therapy and attainment of BP goals may be a determinant in final outcome. The importance of aggressively using combination therapy to achieve target BP rapidly was also underscored in these trials.

The cardiometabolic syndrome is associated with a four‐fold increase in risk of fatal CHD and a fiveto nine‐fold increase in the risk of DM2. ² The JNC 7 guidelines currently recommend lifestyle changes as the first line of therapy in patients with the metabolic syndrome and to start pharmacologic therapy once BP ≥ 140/90 mm Hg. Compelling evidence suggests that vascular abnormalities such as HTN and atherosclerosis precede the onset of DM2 in patients with insulin resistance and by the time diabetes is diagnosed in many patients, HTN is already present. ¹ Furthermore, cardiometabolic risk factors and CVD seem to be concurrent across a spectrum of nondiabetic blood glucose readings. ¹⁰ The JNC 7 does not list the cardiometabolic syndrome as a compelling indication and, by default, a diuretic should then be the medication of first choice.

Use of agents that interrupt the renin angiotensin system appear to be useful in preventing progression to diabetes in patients with HTN and may be of benefit in patients with the metabolic syndrome. The recent Valsartan Antihypertensive Long‐term Use Evaluation (VALUE) ¹¹ trial evaluated patients with HTN on either a valsartan‐based or amlodipine‐based regimen. BP dropped markedly in both groups within the first 6 months to achieve target BPs and was sustained throughout most of the 5 years of follow‐up. Valsartan achieved a 23% relative risk reduction, 13% compared to 16.4% absolute risk reduction (absolute risk difference was 3.3%), in progression to diabetes mellitus when compared with amlodipine. These results suggest that early initiation of aggressive therapy could preempt the progression to diabetes in patients who may have insulin resistance, hence averting the consequences of these comorbidities. The abovementioned results raise several questions. How long should you wait before treatment in a diabetic patient with pre‐HTN? Conversely, how long should you wait to treat a hypertensive patient with a high risk of progression to diabetes?

MOVING THE GOALPOSTS

How rapidly should target BPs be reached once BP therapy is initiated? As a group, these studies suggest that getting to goal within 6 months of initiating therapy may be a key determinant in reducing progression of atherosclerosis, progression to diabetes, and in reducing CVD death. Attaining BP control even with the currently existing guidelines is challenging. That notwithstanding, accumulating evidence suggests that the current targets may be too high for patients with complex HTN and that current practice allows for longer periods of titration to target BP than may be optimal. Individualized risk assessment and treatment is paramount in achieving a reduced risk of cardiovascular complications. Vigilance in identifying patients with complex HTN, achieving control early, and aggressively maintaining BP targets is needed to curtail the rise in adverse cardiovascular events.