Late Acceleration of Treated Uncontrolled Hypertension

A 74-year-old man was referred to the hypertension clinic for evaluation of accelerated hypertension. He stated that he had been on medication for hypertension for approximately 30 years. The initial drug had been atenolol; in approximately 1990 an unknown second drug was added. By patient report, his blood pressure was well controlled. Over the past 2 years, however, his systolic blood pressure had become markedly elevated at home and in the office despite an increasing drug regimen. Chart review revealed a record of isolated systolic hypertension for at least 20 years. Systolic pressure values from the late 1980s until late 2004 had consistently been in the 140- to 150-mm Hg range, with a mean pressure of 146/84 mm Hg in that time period. There was a rise in blood pressure in late 2004 (Figure 1), and mean pressure between November 2004 and April 2007 was 158/85 mm Hg. Six months prior to the consultation, there was a second rise in blood pressure; the mean blood pressure was then 182/78 mm Hg. Sequential blood pressure data from a case study that occurred in 2 phases: (a) long-term, stable, treated uncontrolled hypertension followed by (b) abrupt onset of resistant hypertension. The patient claimed adherence to his medical regimen and checked his home blood pressure a few times weekly with an 8-year-old monitor. Review of his pharmacy record showed that he was filling his prescriptions on time. He stayed away from salty foods and, while not regularly pursuing specific physical exercise, was active in the garden on a daily basis. His weight over the past 20 years had risen from 80 to 82 kg. The past medical history included obstructive uropathy due to benign prostatic hypertrophy with symptoms controlled on terazosin as well as a left carotid endarterectomy in 2006 for asymptomatic carotid stenosis. At the time of his consultation, medications included hydrochlorothiazide 25 mg, atenolol 50 mg, lisinopril 40 mg, amlodipine 5 mg, terazosin 5 mg, clonidine 0.2 mg at bedtime, and simvastatin 40 mg. He had a beer once or twice weekly but had never used tobacco. Baseline laboratory values included hemoglobin, 14.6 mg/dL (normal, 14–18 g/dL); potassium, 3.8 mmol/dL (normal, 3.5–5.0 mmol/dL); fasting glucose, 113 mg/dL (normal, 70–109 mg/dL); low-density lipoprotein cholesterol, 88 mg/dL (normal, <100 mg/dL); and creatinine, 1.0 mg/dL (normal, 0.7–1.3 mg/dL). Results of 12-lead electrocardiography were normal. Studies were obtained to rule out secondary etiologies of hypertension. Findings of both captopril renography and magnetic resonance angiography of the renal arteries were normal. An obstructive sleep apnea study revealed <5 hypopnea/apnea events/h (normal, <5 events/h); morning renin, 3.4 ng/mL/h (normal, 0.65–5.0 ng/mL/h); and aldosterone, 12 ng/dL (normal, 3–34 ng/dL). Data from 24-hour urine collections for total metanephrines and catecholamines were normal. Calcium concentration was 9.7 mg/dL (normal, 8.5–10.7 mg/dL), and thyroid-stimulating hormone level was 2.4 μIU/mL (normal, 0.4–4.0 μIU/mL). Over a period of 3 months, the patient’s regimen was changed to chlorthalidone 25 mg, spironolactone 50 mg, lisinopril 40 mg, amlodipine 10 mg, atenolol 50 mg, and terazosin 10 mg daily, and a blood pressure of 138/78 mm Hg was achieved. Onset of essential hypertension in this patient occurred in his mid 40s. The “control” apparently accepted by his physicians consisted of systolic blood pressure in the 140- to 150-mm Hg range, with a mean of 146 mm Hg. That level of blood pressure was fairly constant over >20 years before acceleration occurred. Despite adherence to a multidrug regimen, his systolic blood pressure had risen to 182 mm Hg, accompanied by asymptomatic partial occlusion of the left carotid artery requiring endarterectomy. Results of an extensive search for superimposed secondary etiologies of hypertension were negative. Therefore, the blood pressure acceleration with target organ damage was attributed to the natural progression of essential hypertension. Would more effective treatment over the long period of time preceding the acceleration have prevented this patient’s higher blood pressure and carotid artery disease? There is evidence from hypertension treatment trials that in addition to the well-known reduction in the hard end points of stroke, myocardial infarction, and cardiovascular mortality, there is also a significant reduction in the acceleration of hypertension associated with treatment. An analysis of 6 placebo-controlled trials identifying blood pressure progression to diastolic levels >110 mm Hg or systolic levels >180 to 200 mm Hg showed progression in 11.2% (1493 of 13,342) of placebo-treated patients compared with 0.7% (95 of 13,389) patients treated with antihypertensive agents.1 Other compilations of hypertension progression without therapy, indicative of natural progression, showed rates of progression of 5.5 to 15.0 per 100 patients during 4- to 5-year trials in elderly hypertensives compared with 4.0 to 17.2 per 100 patients in nonelderly hypertensives.2 There was a high end rate of progression of 17.2 events/100 patients over 5 years in the Oslo trial; mean blood pressure rose in patients whose blood pressure progressed from 158.2/101.1 mm Hg at baseline to 175.1/113.1 mm Hg before drug treatment was initiated.3 In the Oslo trial, the threshold for drug intervention for control group patients was either a systolic pressure ≥180 mm Hg or a diastolic pressure ≥110 mm Hg. There are reasons to believe that the natural history of disease progression when hypertension is untreated has been underestimated. Data are derived from some older trials in which diastolic blood pressure was the primary treatment variable,4-6 though most trials contained information on systolic pressure progression.7-14 Two placebo-controlled trials targeted systolic blood pressure.13, 14 Population studies such as the Framingham Heart Study have clearly shown that past the age of 50 to 55 years, blood pressure progression is predominantly systolic.15 Relevant to the 74-year-old man in this case discussion, a 65-year-old normotensive man has a 62% chance over 10 years of hypertension developing and a 20% chance of stage 2 hypertension developing (≥160/100 mm Hg).16 In addition, most of the early cited hypertension treatment trials excluded patients with target organ damage, such as coronary heart disease or cerebrovascular disease, and included few patients with diabetes. Progression of hypertension in untreated or ineffectively treated individuals would more likely be expected in patients with cardiovascular disease or diabetes. Therefore, for the usual hypertensive patient population with overlapping cardiovascular comorbidities, one would expect a greater treatment effect preventing hypertension progression. In these cases, we are dealing with information from 4- and 5-year treatment trials; the current case discussion applies to suboptimally treated hypertension of 2 decades’ duration. Pathophysiologically, untreated or treated but uncontrolled hypertension may accelerate large artery stiffness, thus promoting a further increase in systolic blood pressure and a “vicious cycle.”17 Arteriosclerosis occurring especially with elevated systolic pressure and aging involves extracellular processes in the media layer of the walls of the aorta and other large elastic arteries where elastin undergoes thinning, fragmentation, fracturing, and replacement with collagen and calcium; arteriosclerosis causes stiffening.18 Past the age of 60, large artery stiffness and consequent early pulse wave reflection from the periphery augments systolic rather than diastolic pressure and is the primary etiology of increasing systolic blood pressure, rather than an increase in peripheral vascular resistance.18 It follows that higher levels of systolic pressure would be more likely to promulgate increased large artery stiffness and further progression of hypertension. When the Framingham cohort was divided into 4 groups according to baseline systolic blood pressure and followed with sequential biannual examinations, patients who had the highest initial systolic pressures had the steepest rate of increasing systolic pressure17 (Figure 2). The systolic blood pressure groups were (1) <120 mm Hg, (2) 120 to 139 mm Hg, (3) 140 to 159 mm Hg, and (4) ≥160 mm Hg. Although the Framingham cohort used in this analysis excluded patients receiving antihypertensive therapy, it has been shown that hypertension progression is potently mitigated by effective therapy and that suboptimal therapy may only be partially effective in preventing progression. Grouped Framingham study data showing average systolic blood pressure levels from all available data from each patient within 5-year age intervals. Initial systolic blood pressure groupings: 1, <120 mm Hg; 2, 120–139 mm Hg; 3, 140–159 mm Hg; 4, ≥160 mm Hg. Reproduced with permission from Franklin et al, 2007.17 Antihypertensive drug therapy slows the underlying disease processes that promote stiffening of the large arteries and the resulting increase in systolic blood pressure. Drug-induced reduction of systolic pressure acts to decrease downstream peripheral resistance to reduce intramural pressure and stretch of the large elastic arteries. Second, small artery vasodilitation reduces the velocity of the reflected pressure wave so that there is reduced augmentation of central aortic systolic pressure.18 Effective drug therapy acts to reduce cardiac afterload and promote the regression of small vessel muscle hypertrophy, in addition to slowing arteriosclerosis. Therefore, more effective drug therapy leading to lower levels of systolic pressure is more likely to prevent hypertension progression than less effective drug therapy. Antihypertensive treatment may also slow or prevent the development of hypertension. The Trial of Preventing Hypertension (TROPHY) demonstrated that even in the prehypertensive range of 130–139/85–89 mm Hg, only 2 years of antihypertensive drug therapy reduced progression to the hypertensive range in 9.8% of individuals 2 years past the discontinuation of antihypertensive therapy.19 TROPHY patients were younger, with a mean age of 48 years, suggesting that mechanisms of increasing peripheral vascular resistance such as arteriolar hypertrophy and endothelial dysfunction in this age range are also amenable to antihypertensive therapy. The primary importance of achieving a blood pressure treatment target is preventing target organ damage. In this case, prior to the development of carotid artery disease, the target was <140/90 mm Hg. The Felodipine Event Reduction (FEVER) trial highlighted the significance of reaching this target.20 In this study of 9711 patients whose blood pressure goal had not been reached with thiazide monotherapy, felodipine was added in the intervention arm compared to placebo in the control arm. After an average of 40 months, the systolic pressure in the control arm was 142 mm Hg compared to 137 mm Hg in the felodipine intervention arm. There were highly statistically significant reductions in the primary end point of fatal and nonfatal stroke (27%; P=.001), as well as the secondary end points of all cardiovascular events (27%; P<.001), all cardiac events (35%; P=.012), and cardiovascular mortality (33%; P=.019)20 in the patients with the lower systolic blood pressure. Practitioners should not be satisfied with systolic blood pressure values in the 140-mm Hg range; blood pressure should be lowered to <140 mm Hg. The rationale for achieving a goal level <140/90 mm Hg in patients with uncomplicated hypertension lies in the prevention of stroke, myocardial infarction, and cardiovascular mortality as hard end points and the prevention of so-called soft treatment end points such as hypertension acceleration. With proven carotid artery disease, the treatment goal for this patient is now <130/80 mm Hg.21 Following 3 months of antihypertensive drug up-titrations at 2- to 4-week intervals, a blood pressure value of 138/78 mm Hg was attained for this case on near-maximal 6-drug therapy. During the >20 years of 2-drug antihypertensive therapy, when the patient had a mean systolic pressure of 146 mm Hg, a goal systolic blood pressure <140 mm Hg probably could have been achieved with the addition of a third agent. Supportive data have been presented to suggest that this patient’s late blood pressure rise may have been avoidable. Long-term blood pressure control may improve aortic remodeling and reduce the long-term stiffness that causes further systolic blood pressure elevation. Acceleration of previously controlled hypertension is an indication to rule out superimposed secondary hypertension,22 as was done in this case. In this clinical situation, it is also important to evaluate medication adherence, address possible lifestyle neglect such as weight gain, and evaluate possible interfering substances (nonsteroidal anti-inflammatory drugs, alcohol, ginseng, etc). It is probably true that blood pressure acceleration that occurs in the context of long-term suboptimal therapy in which goal blood pressure levels are not attained is more likely due to a natural disease progression of essential hypertension, which can be prevented.