Review
Isolated Systolic Hypertension: An Update After SPRINT

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Abstract

Isolated systolic hypertension is the most common hemodynamic form of hypertension in the elderly. With a rapidly aging population, the prevalence of hypertension, particularly isolated systolic hypertension, is expected to increase substantially. This phenomenon of increasing systolic pressure in the elderly is believed to be secondary to pathophysiological changes of aging as well as modifiable risk factors. Isolated systolic hypertension is associated with substantial mortality and morbidity, particularly of cerebrovascular disease. It is a rapidly growing public health concern and its management continues to remain a challenge to practicing physicians. Recent studies like the Systolic Blood Pressure Intervention Trial (SPRINT) and Heart Outcomes Prevention Evaluation (HOPE)-3 have implications for antihypertensive therapy in general and for the management of isolated systolic hypertension in particular. In this article we will review: 1) epidemiology and pathophysiologic mechanisms, 2) impact of isolated systolic hypertension on cardiovascular outcomes, 3) optimal management strategies, and 4) systolic blood pressure goals in the light of SPRINT and HOPE 3 trials.

Section snippets

Epidemiology

The prevalence of untreated hypertensive adults with isolated systolic hypertension according to 1999-2010 National Health and Nutrition Examination Survey data amounts to 9.4%, of which 29.4% occurred in the elderly, ≥60 years, as compared with 6.0% in ages 40-59 years and 1.8% in ages 18-39 years.4, 5 In the elderly population, women, non-Hispanic blacks, and those with only secondary school education were more likely to be affected.5 With more aggressive management of hypertension, the

Pathophysiologic Mechanisms

Isolated systolic hypertension can develop either from “burned out” diastolic hypertension in patients with long-term essential hypertension, or from a de novo increase in systolic BP secondary to increased arterial stiffness in previously normotensive individuals.6 Secondary causes of de novo systolic hypertension include type 1 diabetes, osteoporosis with vascular calcifications, accelerated atherosclerosis from chronic kidney disease, peripheral vascular disease, altered elastin formation

Systolic Blood Pressure, Isolated Systolic Hypertension and Cardiovascular Risk

Systolic BP is a major determinant of cardiovascular risk. In a meta-analysis of individual data of one million adults from 61 observational studies, increase in systolic BP was directly and significantly related to cardiovascular and all-cause mortality, without any evidence of a threshold effect down to at least 115/75 mm Hg.16 Studies evaluating 24-hour ambulatory BP showed similar detrimental effect of elevated systolic BP. A meta-analysis of 20 studies involving 9299 individuals and 11.1

Randomized Control Trials for Isolated Systolic Hypertension

Four landmark randomized trials28, 29, 30, 31 provided ironclad evidence for treatment of isolated systolic hypertension in the elderly (Table 2). The primary end point in all the 4 placebo-controlled trials was incidence of fatal and nonfatal stroke, which was significantly lower in the active treatment arm (Figure 2). All 4 trials defined isolated systolic hypertension as systolic BP ≥160 mm Hg. An individual-patient meta-analysis of 15,693 patients with isolated systolic hypertension from 8

Antihypertensive Agents in Isolated Systolic Hypertension

  • Primary Drugs: Thiazide-like diuretics and Dihydropyridine calcium channel blockers (CCB)

  • Secondary Drugs: Angiotensin-Converting Enzyme inhibitors (ACEi) or Angiotensin Receptor Blockers (ARB)

From the above randomized trials it becomes clear that thiazide-like diuretics (chlorthalidone and indapamide) as well as CCBs of the dihydropyridine type (eg, amlodipine, nitrendipine, nifedipine) substantially reduce the risk of stroke and of other morbid events. Based on the data in aggregate, CCBs and

Drug Combinations for Isolated Systolic Hypertension

  • Primary: CCBs + Thiazide-like diuretics (Indapamide, Chlorthalidone)

  • Secondary: CCBs + ACEi or ARBs, Thiazide-like diuretics (Indapamide, Chlorthalidone) + ACEi or ARBs

The majority of patients eventually require combinations of 2 or more antihypertensive medications to reach goal BP. Evidence from the individual-therapy trials and available combination-therapy trials suggest that in patients who require more than one antihypertensive therapy, a combination of CCBs and thiazide-like diuretics

Drugs to Avoid: Beta-Blockers

Evidence has shown that beta-blockers have little, if any, efficacy in management of hypertension.36 As noted in the isolated systolic hypertension substudy of the Losartan Intervention For Endpoint reduction (LIFE-ISH) trial, atenolol was inferior to losartan for cardiovascular risk reduction.37 In the second Swedish Trial in Old patients with Hypertension (STOP-2) trial subgroup, the combination of diuretics and beta-blockers had the highest events for stroke, compared with ACEi and CCBs.38

Systolic Blood Pressure Goals: Does One Size Fit All?

Optimal or target systolic BP in patients with hypertension has been a topic of intense debate. The prior trials on systolic BP goals not only showed inconsistent results, but were highly heterogeneous in terms of their patient cohorts, methodology, and BP goals. Furthermore, data pertaining to isolated systolic hypertension are limited. The earlier Systolic Hypertension in the Elderly Program (SHEP) trial28 and the HYpertension in the Very Elderly Trial (HYVET)31 found significant benefits of

Isolated Systolic Hypertension in Young and Middle-Aged Individuals

The overall prevalence of isolated systolic hypertension in individuals aged 18-39 years and aged 40-59 years in the US is estimated 1.8% and 6%, respectively. In young individuals, it is thought that the systolic pressure is elevated predominantly in peripheral arteries, and not in central arteries, resulting in the higher amplification of the upper limb arterial pressure pulse wave.49 It has also been shown that young patients with isolated systolic hypertension but low central BP have lower

Conclusions and Perspectives

Isolated systolic hypertension is highly prevalent in the elderly and is a major cause of mortality and morbidity. Blood pressure control rates in these patients remain sub-optimal at present. Appropriate evidence-based management strategies should be employed for management of BP. CCBs and thiazide-like diuretics (chlorthalidone, indapamide) reduce the risk of stroke, and should be considered as first-line agents. Nonetheless, most of the elderly patients require multiple antihypertensives to

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    Funding: None.

    Conflict of Interest: FHM: Consultant or advisory relationships with Daiichi-Sankyo, Pfizer, Abbott, Servier, Medtronic, WebMD, Ipca, ACC, Menarini, Relypsa, University of Utah. CB, SG: None.

    Authorship: All authors had access to the data and a role in writing the manuscript.

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