The 2009 ESH/ESC update consider subclinical organ damage to be a very important component, because asymptomatic alterations of the cardiovascular system and the kidneys are important intermediate stages in the disease continuum that links risk factors such as hypertension to cardiovascular events and death. Moreover, multiple organ damage assessment is useful because of the evidence that in the presence of 2 signs of organ damage (even when present to the same organ), cardiovascular risk may be increased, upgrading the patient to the high cardiovascular risk category. Reassessment of subclinical organ damage during treatment is also crucial because it offers information on whether the selected treatment is protecting patients from progressing organ damage and potentially from cardiovascular events. Analysis of the data provided by some prospective studies indicate that in hypertensive patients, echocardiographic LVH is associated with an incidence of cardiovascular events equal or above 20% in 10 years[63,64]. Furthermore, the relationship of carotid intima-media thickness (IMT) and plaques with cardiovascular events, already discussed in the 2009 update, has been further reinforced by the European Lacidipine Study on Atherosclerosis trial, which have shown that IMT value at the bifurcations and the common carotid exerts an adverse prognostic effect in addition to that of high BP. Finally, renal subclinical organ damage is associated with a 10-year risk of cardiovascular events of 20%. In a prospective cohort of Greek hypertensive patients, a low eGFR was associated with 20% incident cardiovascular event in 10 years.
A reappraisal of trials has underlined that no single trial on hypertension in the elderly has enrolled patients with grade 1 hypertension. Although not evidence based, the 2011 ACCF/AHA Expert Consensus Document suggest to initiate antihypertensive therapy in the elderly according to the same criteria used for younger adults and to use almost the same SBP goal as in younger patients. Interestingly, although in almost all trials the groups of elderly patients randomized to treatment had lower incidence of cardiovascular outcomes, in no trial (except JATOS - the Japanese Trial to Assess Optimal Systolic Blood Pressure in Elderly Hypertensive Patients - with negative results), the on-treatment SBP values were lowered to less than 140 mmHg. Thus, there is no randomized trial in support of lowering SBP to less than 140 mmHg.
Despite the known risk of uncontrolled hypertension in the elderly, there is poor adherence to guidelines. A meta-analysis in 2000 (largely from SHEP, Syst-Eur and Syst-China) pooled 15 693 patients older than 60 years (mean age 70 years) with ISH, SBP more than 160 mmHg, DBP less than 95 mmHg, analyzing the effect of hypertension treatment on cardiovascular outcomes. Average BP was 174/83 mmHg and decrease in BP with treatment was 5.96% for SBP and 4.9% for DBP. Active treatment significantly reduced total mortality by 13%, chronic heart disease death by 18% and stroke by 26%. Clearly, we can conclude that treatment of hypertension in the elderly at least up to 70 years is beneficial to overall mortality. Treatment of hypertension in the elderly patients older than 80 years was not evaluated specifically in prospective trials until the HYVET study was published. The HYVET trial was a randomized prospective trial of 3845 participants older than 80 years. The mean baseline BP was 173/91 mmHg (32% had ISH). Patients were randomized to diuretic or placebo. An angiotensin converting enzyme inhibitor (ACEI) was added if necessary to achieve a goal of BP of 150/80 mmHg. Active treatment was associated with a significant 30% relative risk reduction in fatal and non fatal stroke and 39% reduction in stroke death alone. CVD deaths were reduced by 23%. All cause mortality was also reduced by 23%. The HYVET trial answers a crucial question and gives an end to the dilemma whether hypertensive elderly patients should be treated or not. Physicians can feel comfortable prescribing anti-hypertensives for their elderly patients and know that there will be a mortality benefit. Another question regarding BP treatment in older individuals is whether severe hypertension constitutes an emergency and whether on the other hand there are levels that could be too low that might be associated with increases risk- known as the J-curve phenomenon.
Hypertensive emergency is defined as severely elevated BP in the setting of acute end organ damage. Examples of hypertensive emergencies are acute myocardial infarction, pulmonary edema, cerebral ischemia or hemorrhage, aortic dissection, encephalopathy and progressive renal failure. Aside from the patient who has an obvious hypertensive emergency, how should patients who have asymptomatic severely elevated hypertension be treated? At what BP level does it become admirable to transfer the patient to the hospital? There is no evidence to support the idea that acute reduction of BP reduces cardiovascular events in the short or long term. In fact, many cases of harm have been documented. The mechanism by which acute reduction of BP leads to harm is related to auto regulation of blood flow. Patients, who have elevated BP, often have been present for many weeks or months. Any attempt to lower BP acutely may harm them by offsetting the patient’s adaptive auto regulatory control. Asymptomatic patients who do not have end-organ damage or significant comorbid illnesses should not have acute reduction of BP attempted. Instead, careful titration of antihypertensive medications should be undertaken with plans for close follow-up. Excessively lowering of the BP could be associated with poor outcome in long term (J-curve phenomenon). A Framingham Study in 2004 by Kannel et al suggested that BP was responsible for the increased mortality and not DBP alone.
The therapeutic strategies for hypertension in the elderly as well as the basic effects and the main cardiovascular benefits of the pharmacological agents are summurized in Table 5.
Pharmacological management of hypertension in elderly patients
When lifestyle measures fail to lower BP to goal, pharmacotherapy should be initiated. The safety and efficacy of multiple medication classes has been studied in elderly patients over the last 30 years. Randomized controlled trials have consistently demonstrated that antihypertensive therapy in the elderly is effective in preventing total mortality, stroke and coronary events. Another important consideration is that for most trials, the goal and achieved bp are higher than that recommended by JNC-7, while still showing a significant benefit of treatment.
General principles of pharmacological management: There is often a debate about which antihypertensive drug class should be used first in elderly patients with hypertension. Several classes of antihypertensive drugs are effective in preventing cardiovascular events. Treatment decisions should be guided by the presence of compelling indications such as diabetes mellitus, stroke or HF and by the tolerability of individual drugs or drug combinations. The initial antihypertensive drug should be started at the lowest dose and gradually increased depending on the BP response to the maximum tolerated dose. If the antihypertensive response to the initial drug is inadequate after reaching full dose, a second drug from another class should be added. If the antihypertensive response in inadequate after reaching the full dose of 2 classes of drugs, a third drug from another class should be added.
A common question arising from current clinical practice refers to the threshold BP values for treatment initiation. As mentioned in the ESC 2007 document, the guidelines recommend to start drug treatment in grade 1 hypertensive patients at low or moderate risk when BP is equal or above 140/90 mmHg after lifestyle modifications. These thresholds which have been confirmed in the ESH 2009 update are similar in elderly hypertensives based on the results of the HYVET-trial. Prompter treatment is recommended in grade 2 and 3 of hypertension. In patients with high-normal BP (“pre-hypertension”), drug treatment should be delayed when overall cardiovascular risk is low. As far as goals of treatment are concerned, the ESH 2009 guidelines update document recommends to lower BP to values within the range 130-139 mmHg for systolic and 80-85 mmHg for diastolic, in all hypertensive patients. Furthermore, the concept of lower BP goals in diabetics or very high risk patients is no longer recommended because there is no evidence of a greater benefit. On the other hand, the quantification of the total cardiovascular risk must also include a search for subclinical organ damage.
Pharmacological agents: The JNC-7 trial recommends a thiazide diuretic as initial drug therapy or in combination with other class. Thiazide diuretics control hypertension by inhibiting reabsorption of sodium (Na+) and chloride (Cl-) ions from the distal convoluted tubules in the kidneys by blocking the thiazide-sensitive Na+-Cl- symporter. The term “thiazide” is also often used for drugs with a similar action that do not have the thiazide chemical structure, such as chlorthalidone and metolazone. These agents are properly termed thiazide-like diuretics. Thiazides are preferred because of an extensive volume of data showing that may decrease stroke and CV mortality in elderly patients with hypertension and because of their wide availability and low cost. These agents have benefits that are distinct from their effects on BP and CVD outcomes.
Their effect on calcium reabsorption constitutes the basis for their usefulness in preventing the formation of calcium containing renal stones and may also explain their protective effects on rates of bone mineral loss and prevention of hip fracture[72-74]. Unfortunately, thiazide treatment is associated with various metabolic side effects, including electrolyte abnormalities, dyslipidemia, insulin resistant and new-onset of diabetes mellitus. Whether the metabolic effects of diuretics have adverse consequences for CVD outcomes has been questioned. In Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) study, there was no significant increase in any outcome (stroke, total mortality, CAD, HF, end stage renal disease) in subjects who developed incident diabetes mellitus. In fact, thiazides remained unsurpassed in all clinical outcomes compared with the other drug classes. Only the Avoiding Cardiovascular events through COMbination therapy in Patients LIving with Systolic Hypertension (ACCOMPLISH) trial favored ACEI/CCB combination over the ACEI/THIAZIDE combination in patients with hypertension who were at high risk for cardiovascular events. However, the hydrochlorothiazide dose used (12.5-25 mg/dL) was half the dose used in other trials, indicating the need to titrate to higher doses. Data support the following dosages of thiazides: hydrochlorothiazide 25 to 50 mg/d, indapamide 2.5 mg/d, chlorthalidone 12.5-25 mg/d.
ACEIs can also be considered for first-line or combination therapy, especially if diabetes, HF, post myocardial infarction or chronic disease is present. ACEI block the conversion of angiotensin I to angiotensin II in multiple tissues and thus lower total peripheral vascular resistance reducing BP without reflex stimulation of heart rate and cardiac output. As aging occurs, angiotensin levels are lower and theoretically ACEIs should not be as effective as other therapies, but multiple studies have shown otherwise. Among ACEIs benefits reduction in mortality in patients with MI and left ventricular dysfunction as well as reducing progression of diabetic renal disease are the most important[78,79]. When combination therapies are needed, often for high risk patients, JNC-7 guidelines indicate a strong preference for a thiazide diuretic. The superiority of the amlodipine-based therapy (ACCOMPLISH trial) with respect to the clinical outcomes in this trial suggests that approaches that do not include thiazides may be better for some populations. Nevertheless, these results should not cast doubt on the efficacy of diuretics in reducing the risk of cardiovascular events. In the HYVET trial, mortality was reduced with therapy that combined a diuretic with an ACE inhibitor as compared with placebo. Μoreover,patients with or at risk of sarcopenia may particularly benefit, as ACEIs have been shown to improve muscle strength and working speed in older hypertensive individuals. Therefore, this group of hypertensive may be a good choice for the frail elderly. Finally, the main adverse effects of ACEIs include hypotension, chronic dry cough and rarely angioedema or rash. Renal failure can develop in those with renal artery stenosis. Hyperkalemia can occur in patients with renal insufficiency. Rarely, neutropenia or agranulocytosis can occur. Therefore, close monitoring is suggested during the first months of therapy.
Hypertensive patients with diabetes mellitus, angiotensin receptor blockers (ARBs) are considered first line treatment and as an alternative to ACEIs in patients with hypertension and HF who cannot tolerate ACEIs. Blockage of angiotensin II receptors directly causes vasodilation, reduces secretion of vasopressin and reduces production and secretion of aldosterone. The combined effect reduces BP. The LIFE (Losartan Intervention For Endpoint reduction in Hypertension) study compared losartan with atenolol in patients (age 55 to 80 years) with hypertension and LVH, showing reduced stroke rate in the losartan treated group despite comparable BP reduction in both treatment groups. In MOSES (Morbidity and Mortality after Stroke-Eprosartan compared with Nitrindipine in Secondary Prevention) study, eprosartan reduced stroke by 25% in patients with mean age 68 years. The Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) trial showed similar efficacy between telmisartan and ramipril in elderly hypertensive subjects.
The usefulness of β blockers (reduce the heart rate and cardiac output, inhibit renin release, generate NO, reduce vasomotor tone) as first line treatment of hypertension in older persons has been questioned. Although β-blockers have been used for hypertension in the elderly for years, evidence for benefit has not been convincing. Two large randomized trials, the LIFE study and the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) study, showed superiority of an angiotensin receptor antagonist and respectively an antihypertensive regimen of a calcium antagonist adding perindopril, over therapy initiated by a β-blocker as far as stroke (LIFE) or stroke and mortality (ASCOT) were concerned[84,88]. The 2 large trials have strongly influenced a recent meta-analysis which concluded that β-blocker should not remain first choice in the treatment of primary hypertension. On the basis of a similar meta-analysis, the National Institute for health and Clinical Excellence in the United Kingdom has advised the use of β-blockers as fourth antihypertensive agent. The adverse effects of β-adrenergic receptor blocking drugs can be divided in 2 categories: (1) those that result from known pharmacological consequences of β-adrenergic receptor blockade; and (2) other side-effect that do not appear to result from β-adrenergic receptor blockade. The first category includes bronchospasm, HF, prolonged hypoglycemia, bradycardia, heart block, intermittent claudication, and Raynaud’s phenomenon. Neurological reactions include depression, fatigue, nightmares. Patient’s age does not appear in itself, to be associated with more β-blocker side effects. Side effects of the second category are rare. They include an unusual oculomucocutaneous reaction and the possibility of oncogenesis.
In general, calcium antagonists appear well tolerated by the elderly. They are a heterogenous group of drugs with different effects on heart muscle, sinus node function, atrioventricular conduction, peripheral arteries and coronary circulation. Vascular smooth muscle is more dependent on external calcium entry for contraction whereas cardiac and skeletal muscles rely on a recirculating internal pool of calcium. This preferential effect allows calcium antagonists to dilate coronary and peripheral arteries in doses that do not severely affect myocardial contractility and skeletal muscle. The Syst-Eur study investigated whether antihypertensive treatment could reduce cardiovascular complications in elderly patients with isolated systolic hypertension. It showed that antihypertensive drug-treatment, starting with the dihydropyridine calcium channel blocker nitrendipine, improves prognosis in elderly patients with isolated systolic hypertension.
Direct renin inhibitors, Aliskiren is an orally active direct rennin inhibitor approved for hypertension; 150 mg to 300 mg once daily appears as effective as ARBs and ACEIs for BP management. Combining aliskiren with HCTZ, or amlodipine causes greater BP lowering than with either agent alone. The major side effect is a low incidence of mild diarrhea. Thus far, we know that dual RAS blockade with an ARB and an ACEI is not beneficial in patients like those in ONTARGET trial, and that it has questionable benefit in HF. However, little was known about combining a direct renin inhibitor with either an ACEI or an ARB. The results of the halted ALTITUDE trial showed that the combination of aliskiren with ACEI or ARB in type 2 diabetic patients with high risk for cardiovascular and renal events is contraindicated because of the increased risk for non-fatal stroke, renal complications, hyperkalemia and hypotension in patients taking aliskiren after 18-24 mo[96,97].
Aldosterone receptor antagonists in hypertensive patients decrease BP to limit end-organ damage. Circulating aldosterone levels positively correlate with incident, resistant and obstructive sleep apnea-related hypertension. Both spironolactone and eplerenone are each efficacious in reducing BP; however, there have been a limited number of comparison studies designed to establish drug superiority. Eplerenone improves arterial compliance and reduces vascular stiffness by decreasing the collagen to elastin ratio. Both spironolactone and eplerenone have shown to decrease left ventricle mass. In a small study of patients with resistant hypertension, 6 mo of spironolactone added to diuretic and ACEIs therapy reduced systolic and diastolic BP by 25 and 12 mmHg respectively and the magnitude of the response was not predicted by the plasma aldosterone level. Spironolactone and eplerenone have different side effects profiles, although both share hyperkalemia as a serious side effect. The incidence of spironolactone side-effect associated breast tenderness, gynecomastia, erectile dysfunction and menstrual irregularities increase the rates of medication non-compliance.
Centrally acting agents such as clonidine treats high BP by stimulating a2 receptors in the brain, which decreases cardiac output and peripheral vascular resistance, lowering thus BP. It has specificity towards the presynaptic a2 receptors in the vasomotor center in the brainstem. This binding decreases presynaptic calcium levels and inhibits the release of norepinephrine. The net effect is a decrease in sympathetic tone. Reserpine is another centrally acting agent, whose antihypertensive action is a result of its ability to deplete catecholamines (among other monoamine neurotransmitter) from peripheral sympathetic nerve endings. Both clonidine and reserpine should not be used as monotherapy because they have been associated with a high incidence of adverse effects, including sedation, depression and constipation.
Direct vasodilators such as hydralazine (direct-acting smooth muscle relaxant, acting primarily in arteries and arterioles) and minoxidil may cause headache, fluid retention, tachycardia and angina pectoris. Hydralazine may cause a lupus-like syndrome in 5%-10% of patients during longterm use. Minoxidil (may act as a NO agonist), may cause hirsutism and pericardial effusion[109,110].
In the ALLHAT trial, an α-adrenergic blocking agent, the doxazosin (which inhibits the binding of noradrenaline to the α-1 receptors on the membrane of vascular muscle cells, leading to vasodilation and decreased BP) arm was stopped prematurely due to significant increases in HF (20%), stroke (19%), angina pectoris (16%). These drugs are used for prostate hypertrophy and caution should always be paid for orthostatic hypotension.