Trials in isolated systolic hypertension: An update

Isolated systolic hypertension (ISH) has proved to be a powerful predisposing factor for cardiovascular diseases in the elderly. Recent placebo-controlled interventional trials such as the Systolic Hypertension in the Elderly Program, the Systolic Hypertension in Europe, and the Systolic Hypertension in China showed that the lowering of systolic blood pressure using a diuretic- or a calcium antagonist-based treatment is associated with a decrease in cardiovascular events. Antihypertensive therapy was found especially effective in preventing stroke in the elderly with ISH. A slowing in the progression of dementia was observed in patients randomized to a calcium antagonistbased treatment. Patients at high cardiovascular risk such as those with diabetes benefited the most from treatment. In another trial performed in patients with left ventricular hypertrophy (Losartan Intervention For Endpoint Reduction), a subset of patients had ISH. In those patients, an angiotensin II antagonist-based treatment was superior to a β-blocker-based treatment in preventing cardiovascular complications. The experience accumulated in patients with ISH showed that combination therapy is often required to control blood pressure. Overall, the evidence available today indicates that pharmacologic treatment of ISH markedly improves the outcome of elderly patients.     

The benefit of treating isolated systolic hypertension

Isolated systolic hypertension affects over 15% of all people older than 60 years of age. In the elderly, systolic hypertension is a major modifiable cardiovascular risk factor. Systolic blood pressure is associated with higher risk of an adverse outcome. Diastolic blood pressure is inversely correlated with total mortality, independent of systolic blood pressure, highlighting the role of pulse pressure as risk factor. Three placebo-controlled outcome trials on antihypertensive drug treatment in older patients with isolated systolic hypertension have been published: the Systolic Hypertension in the Elderly Program (SHEP), the Systolic Hypertension in Europe (Syst-Eur) Trial, and the Systolic Hypertension in China (Syst-China) Trial. These three trials showed the benefit of antihypertensive drug treatment. A meta-analysis was done by pooling the patients from these three trials with a subset of patients with isolated systolic hypertension from five other trials in the elderly. The pooled results of 15,693 older patients with isolated systolic hypertension prove that antihypertensive drug treatment is justified if systolic blood pressure on repeated clinic measurements is 160 mm Hg or higher.     

Outcomes of treating hypertension in the elderly: a short commentary on current issues

Because treating hypertension in the elderly so effectively reduces major cardiovascular events, it is vital to diagnose this very common condition early. Much of the hypertension that occurs with aging results from stiffening of the major capacitance arteries, typically marked by high systolic and low diastolic blood pressures. Pulse pressure, derived by subtracting diastolic from systolic values, is a useful index of stiffness, but new noninvasive techniques for measurement of arterial compliance have shown that blood pressures cannot reliably predict the state of the arteries in older people. The Systolic Hypertension in the Elderly Program (SHEP) and the Systolic Hypertension in Europe (Syst-Eur) trial demonstrated that treating hypertension in the elderly with diuretics or calcium channel blockers reduces strokes and cardiac events; these results are also clearly evident in high-risk groups like diabetics. Further analysis of Syst-Eur has suggested that a calcium channel blocker reduces new-onset dementia, while follow-up data from SHEP indicate that a diuretic provides survival and stroke benefits in obese or overweight elderly hypertensives, but not in the lean. In general, comparisons of antihypertensive agents, including diuretics, βblockers, angiotensin-converting enzyme inhibitors, and calcium channel blockers have found similar clinical end point effects. But recently, the Losartan Intervention For End Point Reduction in Hypertension (LIFE) study, performed in patients (average age, 67) with left ventricular hypertrophy and predominant systolic hypertension, showed that the angiotensin receptor blocker losartan was significantly more effective than the β blocker atenolol in reducing such key outcomes as strokes and new-onset diabetes. Even so, careful but effective control of blood pressure in elderly patients, including those over age 80, still remains a critical factor in preventing major cardiovascular events.     

Benefits of antihypertensive drug treatment in elderly patients with isolated systolic hypertension

Isolated systolic hypertension affects over 15% of all people older than 60 years. In the elderly, systolic hypertension is a major modifiable cardiovascular risk factor. Systolic blood pressure is associated with higher risk of an adverse outcome, whereas diastolic blood pressure is inversely correlated with total mortality, independent of systolic blood pressure, highlighting the role of pulse pressure as risk factor. Three placebo-controlled outcome trials on antihypertensive drug treatment in older patients with isolated systolic hypertension have been published: the Systolic Hypertension in the Elderly Program (SHEP), the Systolic Hypertension in Europe (Syst-Eur) Trial and the Systolic Hypertension in China (Syst-China) Trial. These three trials demonstrated the benefit of antihypertensive drug treatment. A meta-analysis was performed by pooling the patients from these three trials with a subset of patients with isolated systolic hypertension from five other trials in the elderly. Antihypertensive treatment based on a calcium-channel blocker may provide additional benefits in diabetic patients and in the prevention of dementia and renal dysfunction. The pooled results of 15693 older patients with isolated systolic hypertension prove that antihypertensive drug treatment is justified if on repeated clinic measurements systolic blood pressure is 160 mmHg or higher.     

Rational for Treatment of Hypertension in the Elderly

Hypertension is a powerful predisposing factor to the major cardiovascular problems common to the elderly, doubling the risk. This increased risk of cardiovascular events exceeds that associated with the existence of hypercholesterolemia, diabetes, and smoking. The decrease in risk ratio with advancing age is offset by the increased cardiovascular disease incidence, resulting in a greater attributable risk, which makes treatment of hypertension more cost effective in the elderly. The prevalence of hypertension is high in the elderly, with about 50% afflicted; 65% of those patients have isolated systolic hypertension (ISH). Hypertension in the elderly often occurs concomitantly with hypercholesterolemia, diabetes, obesity, hypertriglyceridemia, and left ventricular hypertrophy, all of which enhance the risk. Also, 25% of these patients already have manifest cardiovascular disease. These associated cardiovascular conditions and risk factors determine the urgency for treatment and choice of optimal therapy. Antihypertensive trials indicate greater benefit of antihypertensive therapy in the elderly than in the young and have been shown to clearly benefit those with ISH. Thus, hypertension is dangerous in the elderly, is readily controlled, and treatment can provide great benefit in preventing cardiovascular sequelae.     

Systolic hypertension in the elderly. Pathophysiology and management.

Isolated systolic hypertension occurs with increased prevalence in the elderly population. It is characterized by reduced vascular compliance, often combined with increased peripheral resistance. These changes are not specific to patients with systolic hypertension, occurring, perhaps to a lesser extent, in the normotensive aging population as well. Systolic hypertension is associated with a risk of cardiovascular morbidity and mortality that possibly exceeds that associated with systolic-diastolic hypertension. However, until the recent report of the Systolic Hypertension in the Elderly Program, the benefit of treatment of this population was undocumented. The Systolic Hypertension in the Elderly Program demonstrated that lowering of blood pressure with a diuretic, combined, when necessary, with a beta blocker, reduced the rate of myocardial infarction and stroke. Other agents may also be effective in lowering blood pressure, although their ability to reduce cardiovascular morbidity and mortality in this population remains to be documented. The results suggest that pharmacologic treatment be considered for patients older than 60 years whose systolic blood pressure remains above 160 mm Hg (with a diastolic pressure below 90 mm Hg). Whether treatment should be recommended for all patients with systolic hypertension, or, alternatively, for only those at higher risk for cardiovascular events, remains controversial.     

Treatment of isolated systolic hypertension

Isolated systolic hypertension (ISH) is the dominant form of hypertension in the elderly. It is associated with increased arterial pulse pressure, to which an early-returning and magnified pulse-wave reflection makes an important contribution. Treatment of ISH with diuretics, calcium channel blockers (CCBs), and angiotensin II inhibitors is effective in reducing systolic blood pressure, preventing cardiovascular morbid events, and lowering mortality; these agents may have to be used in combination to achieve the systolic blood pressure goal of < 140 mm Hg. Treatment with β-blockers appears to be less effective. The relative efficacy of various classes of antihypertensive drugs for lowering pulse pressure and systolic blood pressure is determined in part by their differing abilities to reduce pulse-wave reflection. In patients with ISH that is refractory to dual or triple therapy, measurement of the reflected wave by applanation tonometry may be useful in determining which additional antihypertensive agent to use.     

Isolated systolic hypertension in the elderly: implications of Systolic Hypertension in the Elderly Program (SHEP) for clinical practice and for the ongoing trials.

The Systolic Hypertension in the Elderly Program (SHEP) was a double-blind placebo-controlled outcome trial on the treatment of isolated systolic hypertension (systolic pressure: 160-219 mmHg and diastolic pressure less than 90 mmHg). From 447, 921 screenes (age greater than or equal to 60 years) 4,736 patients were randomised. A significant reduction of non-fatal stroke (37%), non-fatal myocardial infarction (33%) and left ventricular failure (54%) was observed in the active treatment group. By contrast, the reduction in transient ischaemic attacks (25%), and in total (13%), cardiovascular (20%), cerebrovascular (29%) and coronary (20%) mortality did not reach a level of statistical significance. SHEP is a landmark trial on the treatment of isolated systolic hypertension (ISH) in the elderly. However, the question to what extent the SHEP results can be extrapolated to clinical practice remains open for debate. Indeed, it is possible that due to selection, the SHEP patients were not entirely representative of the elderly with ISH in the population at large. By contrast with previous intervention studies in elderly patients with combined systolic and diastolic hypertension, the SHEP trail did not demonstrate a significant beneficial effect of antihypertensive treatment on any of the cardiovascular mortality endpoints. Confirmation or rejection of the SHEP results in other trials, including the Syst-Eur study, conducted by the rejection of the SHEP results in other trials, including the Syst-Eur study, conducted by the European Working Party on High Blood Pressure in the Elderly and the Chinese trial in elderly ISH patients, is now awaited.     

Calcium channel blockers suppress daily variations of blood pressure in hypertensive patients with end-stage renal diseases

Hypertension is a well-known cardiovascular risk. Patients with end-stage renal diseases frequently suffer hypertension. Furthermore, daily variations of blood pressure are relatively large in patients treated with hemodialysis, partly due to ultrafiltration. Twenty hypertensive patients with end-stage renal diseases whose blood pressure was controlled by a single antihypertensive agent, either angiotensin receptor antagonist (ARB) or calcium channel blocker (CCB), were enrolled into the study. Home blood pressure measurements were also performed. Average systolic and diastolic blood pressures were similar between two agents. However, variations of systolic blood pressure during ARB treatment were greater than those of CCB, and maximal differences in daily systolic blood pressure during treatment with ARB (19?±?7?mmHg) were greater than those with CCB (14?±?6?mmHg, p?p?相似文献   

Isolated systolic hypertension: a new challenge in medicine

In the elderly, isolated systolic hypertension (ISH) is a particularly good predictor of subsequent cardiovascular events. The purpose of this article is to review the evidence provided by the Systolic Hypertension Elderly Program (SHEP) and the Systolic Hypertension in Europe Study (Syst-Eur) on the benefits of lowering systolic blood pressure (SBP) and to report on the preliminary findings of the Maracaibo Aging Study (MAS) on ISH. These two trials, the SHEP using chlorthalidone and atenolol as step 2 and the Syst-Eur using nitrendipine and hydrochlorothyazide as step 2, demonstrated a decrease of more than 30% for all cardiovascular complications, including stroke and coronary events. MAS is a population-based study that included all the subjects older than 55 years of age that resided in a defined area of the city of Maracaibo. There was a high prevalence of ISH (45.7%) being higher among women than in men, and significantly increased with advancing age. SBP was associated with dementia when it was measured by an ambulatory blood pressure monitor (ABPM), while there was no association when it was assessed by the casual method. Diastolic blood pressure (DBP) as casual or measured by ABPM was not related to dementia. In conclusion, ISH is a serious public health problem and benefits from lowering elevated SBP to reduce the risk of cardiovascular events. It was shown there was a strong correlation between high SBP and cognitive dysfunction and this was best demonstrated by using ABPM. Research should address the impact of using modern diagnostic tools and to compare the efficacy of the different types of antihypertensive drugs.     

valsartan in elderly isolated systolic hypertension (VALISH) study: rationale and design.

Although antihypertensive therapy has been proven to reduce cardiovascular morbidity and mortality, it is unclear how much blood pressure should be decreased in elderly patients with hypertension. The Valsartan in Elderly Isolated Systolic Hypertension (VALISH) study is a multicenter parallel-group study comparing the incidence of cardiovascular events between two target systolic blood pressure levels, below 140 mmHg and below 150 mmHg, under treatment with valsartan, an angiotensin II receptor blocker, as an initial antihypertensive drug in elderly patients with isolated systolic hypertension. The number of patients to be recruited is 3,000 and the duration of follow-up is at least 2 years. This 3,000-patient trial was designed with a two-sided alpha level of 0.05 and 80% power to detect the difference in incidence of cardiovascular events between the target blood pressure levels based on estimation of the cardiovascular events ratio as 21.5/1,000 patient-years and 29.1/1,000 patient-years for the two blood pressure levels. The VALISH study, a large-scale investigator-initiated trial in Japan, will determine whether age should be considered in setting target blood pressure in treatment of isolated systolic hypertension in elderly patients.     

Clinical trials in isolated systolic hypertension

Isolated systolic hypertension affects 8% to 15% of all people older than 60 years of age. In the elderly, systolic hypertension is the major modifiable cardiovascular risk factor. Three placebo-controlled outcome trials on antihypertensive drug treatment of this disorder have been published. This article briefly reviews the main findings of each of these three trials and presents pooled estimates of the benefit of antihypertensive drug treatment for elderly patients with isolated systolic hypertension. A total of 11,825 patients were enrolled in the Systolic Hypertension in the Elderly Program (SHEP, n =4736), the Systolic Hypertension in Europe (Syst-Eur, n =4695), and the Systolic Hypertension in China (Syst-China, n =2394) trials. The outcome results of these trials were pooled by calculating the common odds ratio for active versus placebo treatment. The pooled results of the outcome trials in older patients with isolated systolic hypertension prove that antihypertensive drug treatment must be prescribed if, on repeated measurement, systolic blood pressure is 160 mm Hg or higher.     

Calcium antagonists

Calcium antagonists were introduced for the treatment of hypertension in the 1980s. Their use was subsequently expanded to additional disorders, such as angina pectoris, paroxysmal supraventricular tachycardias, hypertrophic cardiomyopathy, Raynaud phenomenon, pulmonary hypertension, diffuse esophageal spasms, and migraine. Calcium antagonists as a group are heterogeneous and include 3 main classes--phenylalkylamines, benzothiazepines, and dihydropyridines--that differ in their molecular structure, sites and modes of action, and effects on various other cardiovascular functions. Calcium antagonists lower blood pressure mainly through vasodilation and reduction of peripheral resistance. They maintain blood flow to vital organs, and are safe in patients with renal impairment. Unlike diuretics and beta-blockers, calcium antagonists do not impair glucose metabolism or lipid profile and may even attenuate the development of arteriosclerotic lesions. In long-term follow-up, patients treated with calcium antagonists had development of less overt diabetes mellitus than those who were treated with diuretics and beta-blockers. Moreover, calcium antagonists are able to reduce left ventricular mass and are effective in improving anginal pain. Recent prospective randomized studies attested to the beneficial effects of calcium antagonists in hypertensive patients. In comparison with placebo, calcium antagonist-based therapy reduced major cardiovascular events and cardiovascular death significantly in elderly hypertensive patients and in diabetic patients. In several comparative studies in hypertensive patients, treatment with calcium antagonists was equally effective as treatment with diuretics, beta-blockers, or angiotensin-converting enzyme inhibitors. From these studies, it seems that a calcium antagonist-based regimen is superior to other regimens in preventing stroke, equivalent in preventing ischemic heart disease, and inferior in preventing congestive heart failure. Calcium antagonists are also safe and effective as first-line or add-on therapy in diabetic hypertensive patients. Heart rate-lowering calcium antagonists (verapamil, diltiazem) may have an edge over the dihydropyridines in post-myocardial infarction patients and in diabetic nephropathy. Thus, calcium antagonists may be safely used in the management of hypertension and angina pectoris.     

Hypertension in the Elderly

Several studies have demonstrated an increased risk of cardiovascular disease (CVD) in relation to high blood pressure in elderly patients aged below 70-75, whereas the risk seemed to decline with age in the older elderly.

Early studies on the effect of treatment of mild to moderate hypertension in the elderly indicated (but did not convincingly show) a reduction of CVD. In the 1980s, both the EWPHE trial (European Working Party on High Blood Pressure in the Elderly) and the HEP study (The Randomised Trial of the Treatment of Hypertension in Elderly Patients in Primary Care) provided evidence of the benefit of treating high blood pressure in the elderly, at least up to the age of 70-74. These results have lately been confirmed by three major trials SHEP (Systolic Hypertension in the Elderly Program), STOP (Swedish Trial in Old Patients with Hypertension) and MRC (Medical Research Council), also including older patients (STOP) and those with isolated systolic hypertension (SHEP). This satisfactory effect was not impaired by a low tolerability of the drugs used (β-blockers and diuretics).

In conclusion, drug treatment with β-blockers and diuretics in hypertensive men and women aged 70 and above confers highly significant and clinically relevant reductions in cardiovascular (especially stroke) morbidity and mortality. The clinical implication of this is that blood pressure lowering therapy should be considered in elderly hypertensives, at least up until they are 80. It should also be remembered that elderly hypertensives often have other diseases as well and that the drug treatment should be adjusted accordingly.     

Is there a preferred antihypertensive therapy for isolated systolic hypertension and reduced arterial compliance?

Isolated systolic hypertension (ISH) is the most common type of hypertension and the most difficult type to control with antihypertensive therapy. ISH, by definition, is wide pulse pressure hypertension resulting largely from excessive large artery stiffness and representing an independent risk factor for cardiovascular disease in the older aged population. Two major intervention studies of ISH have shown significant benefit in reducing systolic blood pressure with active drug therapy, including thiazide diuretics and calcium receptor antagonists. The optimal treatment strategy is to maximize reduction in systolic blood pressure and to minimize reduction in diastolic blood pressure, thereby reducing pulse pressure. All classes of antihypertensive drugs reduce pulse pressure by means of lowering peripheral resistance, but certain drugs like nitrates, angiotensin converting enzyme inhibitors, and other drugs affecting the renin-angiotensin system have multiple actions that improve large artery stiffness and early wave reflection and are especially useful in treating ISH in the elderly.     

Isolated systolic hypertension in the elderly

Opinion statement Isolated systolic hypertension (ISH) is the predominant form of hypertension in persons older than 50 years, who represent the majority of individuals with hypertension. Systolic blood pressure (SBP) determines Joint National Committee blood pressure stage, and therefore the need for therapy, far more often than diastolic blood pressure (DBP). SBP consistently is associated with greater risk for overall mortality, coronary heart disease, stroke, congestive heart failure, renal failure, and other end points. In addition, clinicians are far less aggressive and less successful at controlling SBP compared with DBP. Thus, SBP should be acknowledged as the major criterion that determines diagnosis, staging, and therapeutic management in older individuals. Several recent large, randomized, placebo-controlled trials of drug therapy targeting ISH in the elderly have shown dramatic reductions in cardiovascular end points and mortality. The treatment of patients with ISH must occur within the framework of the larger goals associated with treatment of hypertension generally. Lifestyle modification, including salt restriction and increasing physical activity, may contribute to improvements in arterial compliance and control of ISH in particular. In clinical trials, most antihypertensive agents decrease SBP more than DBP. However, certain drug classes, such as angiotensin-converting enzyme inhibitors and nitrates, have advantageous properties that may make them particularly useful for the treatment of ISH.     

The INSIGHT and NORDIL trials: Are calcium antagonists equivalent to established drug therapies for cardiovascular protection?

Calcium channel blockers have come into worldwide use for treating hypertension and other circulatory disorders. In recent years, results of several observational studies have suggested that these drugs may not be as safe or effective as other available therapies, such as diuretics and &; #x00DF; -blockers, in the prevention of cardiovascular events. The Nordic Diltiazem (NORDIL) and the International Nifedipine GITS Study: Intervention as a Goal in Hypertension Treatment (INSIGHT) studies were the first two randomized interventional trials in hypertensive patients that directly compared the effects of therapy based on calcium antagonists with those of diuretic and ß -blocker-based treatment on major cardiovascular endpoints. Both studies found that the effectiveness of calcium antagonist therapy was similar to that of diuretic and ß -blocker therapy for preventing the composite primary endpoint of fatal and nonfatal stroke, myocardial infarction, and other cardiovascular death. The two studies shared several nonsignificant trends for cause-specific events, including greater stroke prevention and lesser coronary event prevention in the calcium antagonist groups compared with the diuretic and ß -blocker groups. There is not yet sufficient evidence to prove whether cause-specific differences exist. Results of the NORDIL and INSIGHT studies support incorporating calcium antagonist-based therapy as an additional safe and effective approach for preventing blood pressure-related illness and death.     

Hypertension and the elderly: more than just blood pressure control

Hypertension is a major risk factor for cardiovascular disease in both young and elderly persons; therefore, good blood pressure control is at the center of improved cardiovascular health. The recently issued seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure and the European Society of Hypertension/European Society of Cardiology 2003 guidelines for hypertension management emphasize the importance of treatment efficacy rather than age in treating elderly persons with hypertension. Most hypertension clinical trials have been carried out with younger hypertensives, but this is changing with trials such as the Systolic Hypertension in the Elderly Program, the first Swedish Trial of Old Patients With Hypertension, and the Systolic Hypertension in Europe trial. These trials have clearly demonstrated the benefits of good blood pressure control in reducing the risk of stroke in elderly persons. With many safe and effective antihypertensive drugs on the market, the question becomes how elderly persons should be treated. Elderly patients often have isolated systolic hypertension, which is related to loss of arterial elasticity or compliance with aging and is more recalcitrant to treatment than essential hypertension. In addition, with advancing age there is the likelihood that other disease states are present in addition to hypertension. The newer antihypertensive drugs that interfere with the renin angiotensin system, such as angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers, have the potential of improving cardiovascular outcomes in elderly persons in addition to offering effective blood pressure reduction. Their use should be considered within a comprehensive risk assessment that includes individualized risk-benefit considerations.     

Overview of the outcome trials in older patients with isolated systolic hypertension

AIMS: Isolated systolic hypertension affects over 8 to 15% of all subjects older than 60 years. In the elderly, systolic hypertension is the major modifiable cardiovascular risk factor. Three placebo-controlled outcome trials on antihypertensive drug treatment of this disorder have been published. The aim of this article was to shortly review each of these three trials and to present the pooled estimates of benefit of antihypertensive drug treatment in isolated systolic hypertension in the elderly. METHODS AND RESULTS: The Systolic Hypertension in the Elderly Program (SHEP) in the United States, the Systolic Hypertension in Europe (Syst-Eur) trial and the Systolic Hypertension in China (Syst-China) trial published their main findings in 1991, 1997 and 1998, respectively. The outcome results of these trials were pooled by calculating the common odds ratio for active versus placebo treatment for five major end-points. Zelen's exact test for homogeneity did not reach statistical significance for any of the end-points considered. Thus, the hypothesis of a common underlying treatment effect across the three trials was not rejected. Overall, active treatment compared with placebo, reduced all-cause mortality by 17%, cardiovascular mortality by 25%, all cardiovascular end-points by 32%, total stroke by 37% and myocardial infarction including sudden death by 25%. CONCLUSIONS: The pooled results of the outcome trials in older patients with isolated systolic hypertension prove that antihypertensive drug treatment must be prescribed, if on repeated measurement systolic blood pressure is 160 mm Hg or higher.     

Hypertension in older people: part 2

There is overwhelming evidence that pharmacologic treatment of isolated systolic hypertension (ISH) (systolic blood pressure >or=140 mm Hg and diastolic blood pressure <90 mm Hg) reduces cardiovascular events and extends longevity in the elderly; in the very old (80 years or older), the evidence supports decreased incident stroke and heart failure, but is less convincing in terms of longevity. Thus, the inherent increased risk for ISH vascular events highlights the importance of its control. Importantly, ISH in the elderly, primarily related to large artery stiffness, remains more difficult to control than diastolic hypertension in the young, which is primarily related to increased peripheral vascular resistance. Appropriate lifestyle and pharmacologic intervention is indicated in individuals with systolic blood pressure >or=140 mm Hg in general and >or=130 mm Hg in persons with diabetes or chronic kidney disease. Lifestyle intervention may reduce the need for extensive antihypertensive therapy and minimize associated cardiovascular risk factors. To date, only a small percentage of older ISH patients are being treated to goal. Reaching target systolic blood pressure levels most often requires the use of polypharmacy that includes a diuretic and perhaps specific agents that target arterial stiffness and early wave reflection.