(1)
University of Ottawa The Ottawa Hospital, Ottawa, ON, Canada
Relevant Key Issues
There are more than one billion individuals with hypertension worldwide; the number is predicted to grow to 1.56 billion by 2025 (Kearney et al. 2005).
Unfortunately there are only four classes of antihypertensive agents available (only four drugs with many reduplications) and the old well-tried agent beta-blockers have been retired by the JNC8 (2014) mainly because of the results of RCTs in which the most ineffective beta-blocker, atenolol, was used. There are > 6 beta-blockers available, but of the 10 or more hypertensive randomized clinical trials (RCTs), atenolol was the choice beta-blocker in >90 % of trials (see Table 9-1 ). The JNC8 panelist and guideline providers in many countries fail to understand that beta blockers have subtle and important differences (Khan 2005) The author stated in the sixth edition of this book (2003) “the use of atenolol in clinical trials should be curtailed”. Diuretics are no longer first line according to the JNC8 because of the notion they cause diabetes and are mildly acting antihypertensive agents. In essence two agents to treat the many. This chapter gives practical guidance to clinicians that should prove helpful in clinical practice. Fortunately, calcium antagonists are very effective antihypertensive agents.
More than 60 million Americans, 20 % of the population, have hypertension that requires drug therapy. At age 65–75, more than 40 % of individuals worldwide have hypertension. The prevalence of hypertension in industrialized countries in general is similar to that in the white population of the United States.
Most important, we only have four groups of drugs: diuretics, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, [or angiotensin 11 receptor blockers (ARBs)], and calcium antagonists to treat this most common condition that leads to devastating events, particularly cardiovascular death and disability. I have purposely left out centrally acting agents (methyldopa and clonidine) and alpha-blockers because their use is limited to a few selected individuals. Methyldopa is used mainly in pregnancy.
It must be emphasized that ACE I/ARBs are excellent, well-tested, but mild antihypertensive agents, and that calcium antagonists are the most powerful of the four antihypertensive agents available for management of moderate and severe hypertension. We would be lost if these agents were not part of our antihypertensive armamentarium but it is illogical to demote beta-blockers to third or 4th line therapy they can be used as first or second line in many depending on age and ethinicity.
ACE inhibitors and the identically acting ARBs are a major advance but represent a single class of agent. Importantly some ARBs (telmisartan, olmesartan) have come under scrutiny; see later discussion and Chap. 4.
Calcium antagonists are the most effective antihypertensive agent available but are not superior to the two older classes of agents, beta-blockers and diuretics, when used as monotherapy to treat mild hypertension depending on the age and ethnicity of the individual. Mild hypertension is common and treatment choice can be individualized.
Alpha-blockers cause heart failure (HF) and are not recommended agents because they cause heart failure (ALHAT 2000)
In clinical practice, patients who cannot tolerate one or two of the four types of agents are frequently encountered, and many patients require three agents to attain adequate control.
Thus, drug choice is limited. This situation will change only if pharmaceutical companies and experts who formulate hypertension therapeutic guidelines will admit that after more than 60 years of intensive research and numerous RCTs, only four antihypertensive agents are available. The recognition of the truth should promote more intensive research to discover new groups of agents or innovative strategies to add to our present armamentarium of four drug classes.
The organizers of RCTs must provide sound methodology, which has been lacking in many such trials (see the later criticisms of RCTs).
For example, the beta-blocker atenolol is the main beta-blocker that has been compared with other agents in RCTs done from 1984 to 2005.
Most important, Trialists and the JNC8 expert panelists (2014) have failed to recognize that the non-lipid-soluble atenolol is not as cardioprotective as timolol, carvedilol, bisoprolol, propranolol or metoprolol; the only beta-blockers shown in RCTs to be cardioprotective . Beta-blockers have subtle and important differences (Khan 2005, p 150). The use of atenolol in clinical trials should be curtailed (Khan 2003 p 502); this widely prescribed beta-blocker should become obsolete (Khan 2011 p 556) (see Chaps. 1 and 2).
The author often used atenolol from 1974 to 1984 and has nothing to gain from asking clinicians not to prescribe atenolol (except for selected cases of hypertension in pregnancy).
It is surprising that the experts who constructed the recent hypertensive guidelines, (JNC8 2014), fail to understand the subtle but important differences that exist between the available beta-blocking agents.
“The JNC8 panel did not recommend beta-blockers for the treatment of hypertension (first, second, or third line) because in one study use of the beta-blocker atenolol “resulted in a higher rate of the primary composite outcome of cardiovascular death, MI, or stroke compared to use of an ARB a finding that was driven largely by an increase in stroke” (Dahlöf 2002 Life study). In that study (LIFE), 204 losartan and 234 atenolol patients died from cardiovascular disease (p = 0.206); a nonsignificant change in cardiovascular death. Myocardial infarction (nonfatal and fatal) occurred in 198 and 188, respectively (1.07, 0.88–1.31, p = 0.491), a nonsignificant finding (Dahlöf et al. 2002).
Yet another misguided recommendation by the JNC8
In the large Captopril Prevention Project (CAPP 1999) study of captopril versus diuretic and beta-blocker, fatal and nonfatal stroke was increased in the captopril group ( p = 0.044), with no significant differences in other events. A result perhaps as spurious as the LIFE study.
In the large well-run PRoFESS RCT, telmisartan failed to decrease recurrent stroke (Yusuf et al. 2008). ARBs are not as useful as proclaimed.
Others have stated their surprise at both the JNC8 and UK guidelines. Results from LIFE cannot be extrapolated to the general population; the mean age in THE LIFE STUDY was 66.9 years (Morales-Salinas et al. 2014). Beta-blockers are effective in white patients with age less than and older than 60 years and in older black patients with hypertension.
Dickerson et al. (1999) showed in an excellent study that beta-blocker therapy was equal to that of ACE inhibitor monotherapy in younger white patients.
In the ACCOMPLISH RCT trial, investigators assigned 11,506 patients with hypertension who were at high risk for cardiovascular events to receive treatment with either benazepril plus amlodipine or benazepril plus hydrochlorothiazide. The primary end point was the composite of death from cardiovascular causes, nonfatal MI, nonfatal stroke, hospitalization for angina, and coronary revascularization (ACCOMPLISH Trial Investigators, Jamerson et al. 2008).
After a mean follow-up of 36 months, the trail was halted. There were 552 primary-outcome events in the benazepril–amlodipine group (9.6 %) and 679 in the benazepril–hydrochlorothiazide group (11.8 %), representing an absolute risk reduction with benazepril–amlodipine therapy of 2.2 % and a relative risk reduction of 19.6 % (hazard ratio, 0.80, 95 % confidence interval [CI], 0.72–0.90; p < 0.001).
For the secondary end point of death from cardiovascular causes, nonfatal MI, and nonfatal stroke, the hazard ratio was 0.79; (p = 0.002). The benazepril–amlodipine combination was superior to the benazepril–hydrochlorothiazide combination in reducing cardiovascular events (ACCOMPLISH Trial Investigators 2008).
There is little doubt that the combination of the calcium antagonist amlodipine and ACE inhibitor is most useful but treatment must still be individualized.
Consider the following:
Hypertension is the leading cause of cardiovascular disease (CVD) morbidity and mortality.
The prevalence of left ventricular hypertrophy (LVH) as a function of blood pressure (BP) has been proved. The incidence of myocardial infarction (MI) in Framingham subjects with hypertension shows a stepwise increase in risk as BP rises. In more than 40 % of patients with acute MI, an antecedent history of hypertension is obtained. MI is a critical factor in the development of heart failure (HF).
Renal failure caused by renal diseases is often nonpreventable, but that caused by hypertension is. The risk of renal failure is increased in patients with diabetes and in patients of African origin. In virtually all patients with renal failure regardless of cause, antihypertensive agents are administered to maintain a goal BP less than 130 mmHg. Often three or four agents are required.
Most physicians are cognizant of the aforementioned statements, but few are aware of the following distressing facts:
Studies indicate that about 66 % of elderly patients with HF had antecedent hypertension. The bulk of HF is related to hypertension and MI. The message is that effective hypertension control is the single greatest means to prevent diastolic and systolic HF (Fig. 8-1). Heart failure with preserved ejection fraction (HFPEF) has no effective therapy, and prevention is the key (see Chaps. 12 and 13). Interestingly the unique beta-blocker nebivolol in the SENIORS (2009) study has shown salutary effects in patients with HFPEF.
Fig. 8-1.
Common detrimental effects of hypertension. Asterisk: Not well appreciated: epidemic of atrial fibrillation with its management problems.
Hypertension is a common underlying cause of atrial fibrillation, which is the most common sustained arrhythmia encountered in the office and emergency room.
In North America, <40 % of hypertensive patients have their BP controlled to goal.
This chapter discusses antihypertensive agents and emphasizes
Which drugs are best for the management of mild hypertension in younger and older white and black patients. BP reductions caused by antihypertensive agents differ in different ethnic groups and in younger and older patients.
Which drugs are best for patients with major risk factors, target organ damage, and coexisting disease: ischemic heart disease (IHD), diabetes, and hyperlipidemia. These three conditions markedly increase the risk of cardiovascular death. The risk of cardiovascular morbidity and mortality is determined not only by the BP but also by the presence or absence of these coexisting diseases, target organ damage, and risk factors (Table 8-1). Risk stratification is necessary for the formulation of appropriate antihypertensive therapy.
Table 8-1
Major risk factors, target organ damage, and coexisting disease
Major risk factor
Target organ damage
Coexisting disease
Smoking
Heart failure
Diabetes
Age
LV dysfunction
Hyperlipidemia
Men >45 years
LV hypertrophy
IHD
Women > 55 years
Retinopathy
Angina
Family history of IHD or stroke
Renal insufficiency
Silent ischemia
Men <55 years
MI
Women < 65 years
Previous CABG
LV dysfunction
Stroke or TIA
Nephropathy
Peripheral vascular disease
Controversies
ARBs may not be as cardioprotective as shown for ACE inhibitors.
The widely held notion that ACE inhibitors or ARBs reduce the incidence of diabetes and beta-blockers and diuretics increase the incidence is false. See Chaps. 2, 4, and 9. The results of the Dream trial and the study by Hanley et al. (2010) should provide core knowledge for Trialists who have incorrectly reported an increase incidence of diabetes caused by some drugs and a reduction caused by ACE inhibitors and ARBs.
Telmisartan therapy for 56 months, although shown in ONTARGET (2008) to be equivalent to ramipril surprisingly, had no significant effect on the primary outcome, hospitalizations for HF in TRANSCEND (Yusuf et al. 2008). In addition, there was no reduction in total mortality. In the large well-run PRoFESS RCT, telmisartan failed to decrease recurrent stroke (Yusuf et al. 2008).
The safety of the angiotensin receptor blocker olmesartan is questionable after two ongoing trials among patients with type 2 diabetes suggested increased risk for cardiovascular death with the drug.
Definitions
It is generally accepted that systolic hypertension is as important as diastolic hypertension.
Isolated Systolic Hypertension in Older Patients
Isolated systolic hypertension is defined as systolic BP > 140 mmHg and diastolic BP < 90 mmHg present in the absence of target organ damage and coexisting disease (see Table 8-1). Systolic hypertension in individuals aged over 65 years is a major cause of stroke, left ventricular failure (LVF), and mortality from IHD.
The prevalence of high BP in African Americans is among the highest in the world, and organ damage occurs earlier in these patients than in whites.
In approximately 95 % of individuals, hypertension exists without a known cause and is termed primary (essential) hypertension. In the remaining 5 %, hypertension is secondary to known causes (Table 8-2).
Table 8-2
Causes of secondary hypertension
Cause
%
Renal parenchymal disease
3
Renal vascular disease
1
Cushing’s syndrome
0.1
Pheochromocytoma
0.1
Primary hyperaldosteronism
0.1
Coarctation of the aorta
0.1
Estrogens
0.4
Alcohol
0.2 or more
Proper technique for BP measurement is essential for adequate diagnosis and patient care.
The results of the Hypertension Optimal Treatment (HOT) trial (Hansson et al. 1999 ) indicate that, in patients with diastolic BP mean 105 mmHg, it is safe to decrease the diastolic BP to <90 mmHg; further lowering to <85 mmHg did not result in a significant decrease in mortality or event rates but was not harmful. In diabetic patients, a decrease in diastolic BP to ≤80 mmHg resulted in a 51 % reduction in major cardiovascular events compared with target group ≤90 mmHg.
Pseudohypertension
Pseudohypertension is a false reading of high blood pressure. It is not unusual for this to occur in patients with arteriolosclerosis, calcification, and diffuse hardening of the arteries, particularly in the upper limbs. With hardening of the arteries, the rigid, pipe-like arteries resist compression by the sphygmomanometer cuff, and the pressure in the cuff wrapped around the arm fails to constrict and collapse the brachial artery. Because of this, blood continues to flow through the artery into the forearm, causing a false high reading. A reading in the range of 180–220 mmHg is not unusual (Zweifler and Shahab 1993).
Pseudohypertension should be excluded in elderly individuals whose brachial arteries characteristically feel rigid and pipe-like and in individuals who have no effects of hypertension after several years of abnormal readings, such as evidence of hypertension in the retina or cardiovascular or renal disease.
Pseudohypertension may also be suspected in these individuals with blood pressure apparently resistant to therapy and in those who develop dizziness and lightheadedness related to change in posture. Recordings over a period of weeks in the home, particularly with a simple finger or wrist blood pressure measurement, should resolve the diagnosis of pseudohypertension in virtually all patients.
Home Measurements
Home measurements of blood pressure are crucial for the adequate management of hypertension in more than 33 % of hypertensives. A record of home measurements verified by measurements outside the physicians’ office is an important strategy to prevent overmedication. Measurements in the home have been shown to give virtually all of the information provided by ambulatory blood pressure monitoring. Home blood pressure measurements are strongly indicated for the following:
To assist the physician with the diagnosis of borderline or stage 1 hypertension (see stages and classification given above)
To exclude short-term hypertension that may occur for a few months because of stressful situations at work or at home and do not require lifelong medications
To exclude white-coat hypertension
To exclude pseudohypertension in the elderly
To monitor response to therapy to avoid the addition of another antihypertensive agent to achieve control.
Nondrug Therapy
Nondrug therapy should be tried rigorously before drug therapy in all patients with mild hypertension. Nondrug therapy—low-sodium diet, weight reduction, cessation of smoking, reduction in alcohol intake, removal of stress and/or learning to deal with stress, relaxation, exercises, and a potassium-enriched diet—may result in adequate control of hypertension in up to 40 % of patients with stage 1 or isolated systolic hypertension in the elderly. In addition, low saturated fat intake is often necessary because of coexisting hyperlipidemia, which increases risk.
Which Drugs to Choose
The physician should strive for monotherapy in the treatment of mild primary hypertension whenever possible. If the choice of initial agent is based on age and ethnicity, about 45 % of patients attain goal BP < 140 mmHg systolic with monotherapy. There is no justification to strive for a systolic blood pressure <130. A goal of 130–140 is acceptable.
The JNC8 advises a goal <150 mmHg. A state-of-the-art review emphasizes that this new goal has been criticized by many. Certain groups have opposed the decision to initiate pharmacologic treatment to treat to a goal systolic BP of <150 mmHg in the general population age >60 years (Krakoff et al. 2014)
The association of Black cardiologists issued a statement “we strongly disagree with the new 2014 recommendations to raise the threshold for initiating drug treatment and systolic blood pressure goal for older persons, specifically because of the implications for women who comprise the majority of this elderly hypertensive population ” (Gillespie et al. 2014).
It is advisable to give a trial of individual agents before using combinations of drugs or fixed-dose combinations. A combination, however, of two agents at low dose may achieve the therapeutic goal with less potential for adverse effects.
The patient should have a thorough understanding of the problems associated with drug therapy to facilitate acceptance and compliance during medication changes.
It is important for the physician to consider the efficacy and the pharmacologic and adverse effects of the antihypertensive agent to be chosen, as well as the cost to the patient and the ability of the drug to prolong life.
Recommendations for Patients Without Coexisting Disease
Mild Primary Hypertension in Younger Patients: BP 140–160 Systolic
There is abundant evidence from RCTs that whites and African Americans differ in their response to antihypertensive agents. Materson and Reda (1993, 1994) from their study concluded that the effective response to treatment with diltiazem, atenolol, diuretic, and captopril were as follows:
Younger blacks 70, 51, 47, 43;
Older blacks 84, 44, 63, 33;
Younger whites 57, 64, 32, 61 ;
Older whites 71, 72, 68, 61
the weakly effective beta-blocker, atenolol, gave the best response in younger and older white patients.
Deary et al. (2002) completed a double-blind placebo-controlled crossover comparison of five antihypertensive drugs (amlodipine, doxazosin, lisinopril, bisoprolol, and bendrofluazide) and placebo in 34 young nonblack hypertensives and showed that bendrofluazide performed significantly worse ( p = 0.0016) and a beta-blocker, bisoprolol, significantly better ( p = 0.004). Note the beta-blocker used was not atenolol, the favorite of Trialists; this drug that has given beta-blockers a foul name and conjured incorrect notions in the heads of experts who attempt to produce guidelines for clinicians worldwide.
Dickerson et al. (1999) undertook a crossover rotation of the four main classes of antihypertensive drugs in 40 untreated young white hypertensive patients < age 55 to assess the response rate with monotherapy achieved by a systematic rotation 36 patients completed all four cycles. Success of monotherapy was achieved (p = 0.0001); in half the patients, BP on the best treatment was 135/85 mmHg or less.
The responses to the ACE inhibitor or beta-blocker pair were, on average, at least 50 % higher than those to the calcium antagonist/diuretic pair.
Thus beta-blockers are proven antihypertensive agents with effectiveness equal to that of ACE inhibitors or diuretics, depending on age and ethnicity. ACE inhibitors and ARBs are weak antihypertensive agents, and achieve control in < 45 % of patients with mild hypertension; the addition of a diuretic improves effectiveness to ~ 66 %. These agents are overused instead of a beta-blocker or diuretic as first line; it is still useful in clinical practice to think of first or second line choices.
Recommendations for White Patients Younger than Age 65
It may appear old fashioned to recommend beta-blockers and diuretics as first-line agents, but the scientific evidence gleaned from the aforementioned three sound studies and carefully conducted meta-analysis of RCTs reemphasizes their efficacy, safety, and costs (Staessen et al. 2001).
Importantly, calcium antagonists significantly increase the risk of HF in patients older than age 70 (ALLHAT 2002); see Chap. 9 and Table 9-2.
Alpha-blockers increase the risk of HF (ALLHAT 2000) and have deleterious effects on the cardiovascular system. A warning was issued by the American College of Cardiology following the ALLHAT findings in 2000.
ACE inhibitors are more effective than diuretics in younger whites. Recommendations are given in Table 8-3.
Table 8-3
Choice of drug for the treatment of mild primary hypertension based on age and ethnicity
White patients younger than age 65
1. Beta-blocker: bisoprolol, carvedilol, metoprolol (Toprol XL), or nebivolol preferred over other beta-blockers: monotherapy success in ~50 % in this age and ethnic category: Warning: avoid atenolol, see text.
ACE inhibitor: monotherapy success in ~45 %; often requires combination with diuretic to achieve goal BP
But addition of amlodipine is advisable; see ACCOMPLISH trial 2008 success with amlodipine benazepril combination
2. Diuretic: monotherapy success in ~33 %
3. Beta-blocker or ACE Inhibitor/ + diuretic
4. Calcium antagonist: success in ~50 %
5. Combinations at smaller doses advisable
Black patients younger than age 65
1. Calcium antagonist: monotherapy success in ~70 %
2. Beta-blocker (bisoprolol, carvedilol, metoprolol extended release [Toprol XL]): success in ~50 %; avoid atenolol
3. Calcium antagonist + beta-blocker success in >90 % (avoid verapamilb)
4. Diuretic: success in ~33 %
White patients older than age 65
1. Diuretic: monotherapy success in ~50 % (first choice because of safety) older than 80, diuretic first choice
2. Beta-blocker: carvedilol, bisoprolol, metoprolol extended release, or nebivolol; avoid atenolol; success expected in ~ 60 %; second choice because safer than calcium antagonists in the elderly
3. ACE inhibitor: success in > 50 %a
4. Calcium antagonist (avoid verapamil): success in ~60 %
5. Calcium antagonist + ACE inhibitor useful as shown in ACCOMPLISH trial
Black patients older than age 65
1. Calcium antagonist (avoid verapamil): success in ~70 %c
2. Diuretic: success in ~50 %; safe agent tried first
3. Betablocker + diuretic ~70 %
Diuretic + calcium antagonist ~80 %
4. ACE inhibitor ~50 % but risk angioedema
AGE. 80–85: small dose diuretic Indapamide : see HYVET study
But beta-blocker has a definite role: e.g., bisoprolol 2.5–5 mg daily, see text
Recommendations for Younger Black Patients.
Calcium antagonists are the most effective agents, followed by a non-atenolol beta-blocker; the latter may be tried first because these agents are safe and inexpensive and are particularly useful in patients with diabetes; they do not cause diabetes as proclaimed by experts [see the United Kingdom Prospective Diabetes Study Group (UKPDS) and discussion in Chaps. 2, 9, and 22].
Mild Primary Hypertension in Older Patients
Recommendations for White Patients Age 65–80.
Goal systolic <140; but caution is needed to prevent falls and in some patients a treatment goal to <150 is acceptable.
There is no sound evidence to support national committees’ choice of calcium antagonists for the management of isolated hypertension in elderly whites. Beta-blockers are as effective (Materson et al. 1993 ; HANE 1997) and are safer and much less expensive. Beta-blockers are safe in patients aged 65–85 years, and the safety and ability of these drugs in very elderly post-MI patients, and to prevent HF (CAPRICORN 2001; COPERNICUS 2001), have been endorsed in RCTs. Also beta-blockers are widely used in patients of age 65–85 with atrial fibrillation. Thus safety is assured, whereas calcium antagonists may cause heart failure and falls causing serious injuries. Calcium antagonists the most effective antihypertensive agents do cause heart failure, a condition not uncommon in the elderly.
The JNC8 experts have ignored the sound findings of ALLHAT in which amlodipine and nifedipine carried a 32 and 46 % risk for heart failure compared with diuretic therapy (Table 9-2)
Staessen et al. (2001) analyzed nine randomized trials comparing treatments in 62,605 hypertensive patients.
Results:
Compared with old drugs (diuretics and beta-blockers), calcium-channel blockers and ACE inhibitors offered similar overall cardiovascular protection.
There was a higher risk of stroke in patients for whom captopril was randomly assigned .
Increase in fatal myocardial infarction on treatment with nifedipine GITS.
Overall cardiovascular risk did not differ between patients randomized to diuretics or beta-blockers compared with those allocated initial treatment with calcium-channel blockers or ACE inhibitors.
In patients randomized to calcium-channel blockers, reduction in risk of stroke was greater, p = 0.03 than in those in whom treatment was started with old drugs.
In this excellent meta-analysis by Staessen and associates, the authors concluded: “All antihypertensive drugs have similar long-term efficacy and safety,” but in the same article indicated that new drugs significantly increased the risk of HF.
HF is a common cause of morbidity, hospitalization, and death; effective control of hypertension is necessary to stem the epidemic of HF. In the Intervention as a Goal in Hypertension Treatment (INSIGHT 2000) study, among primary end points HF and MI were statistically more frequent in the Adalat XL group. In the Prospective Randomized Amlodipine Survival Evaluation (PRAISE study 1996), pulmonary edema was more frequent in the amlodipine-treated group. In the Multicenter Diltiazem Postinfarction Trial of non-Q-wave MI (1988), diltiazem increased the risk of HF.
These findings are not surprising because calcium antagonists possess significant negative inotropic effects. Elderly hypertensive patients are at a higher risk of HF and MI than younger patients; thus, although calcium antagonists are highly effective antihypertensives in the elderly, beta-blockers, diuretics, and ACE inhibitors are preferred because these drugs have proved useful in the prevention and management of HF. The combination of ACE inhibitor and beta-blocker is not considered complementary, because these drugs do not enhance antihypertensive effects. However, they are both cardioprotective and deserve a clinical trial. Nebivolol and valsartan fixed-dose combination proved to be an effective and well-tolerated treatment option for patients with hypertension (Giles et al. 2014). But it is not advisable to combine valsartan with a beta-blocker because mortality and morbidity are increased as shown in an RCT. In Val-HeFT, valsartan when combined with a beta-blocker caused significantly more cardiac events. A total of 5,010 patients with HF class II, III, or IV were randomly assigned to receive 160 mg of valsartan or placebo twice daily. There was no reduction in all cause mortality. The incidence of the combined end point, however, was a modest 13.2 % lower with valsartan than with placebo (p = 0.009), predominantly because of a lower number of patients hospitalized for heart failure: 455 (18.2 %) in the placebo group and 346 (13.8 %) in the valsartan group (p < 0.001). Overall mortality was not reduced by valsartan administration (Cohn and Tognoni 2001).
In VALIANT (2003): a clinical trial of valsartan, captopril, or both in MI complicated by HF, left ventricular dysfunction, or both, during a median follow-up of 24.7 months, total mortality was not reduced by valsartan: 979 patients in the valsartan group died, as did 941 patients in the valsartan-and-captopril group and 958 patients in the captopril group. There was no placebo group.
The JNC8 (2014) guidelines are flawed and should be revised.
In the SHEP study, atenolol was the second agent used, after a diuretic. After 5 years of follow-up, IHD was reduced by 25 %, with a major reduction in stroke. The Swedish Trial in Old Patients with Hypertension (STOP 2 1999) in the elderly showed a significant reduction in mortality and strokes as a result of beta-blocker therapy.
Recommendations for Elderly Patients of African Origin.
Goal in the majority should be <140 systolic and in all ethnic groups, selected individuals over age 75 a goal of <150 is acceptable in the absence of heart or renal failure.
A diuretic and calcium antagonists have been shown to have better antihypertensive effects than beta-blockers and ACE inhibitors and are recommended. However, caution is required in patients with ejection fraction <45 % because the risk of HF may increase with long-term calcium antagonist therapy. Thus, a diuretic is the first choice in elderly patients of African origin.
Recommendations for All Elderly Over Age 80.
Advice is based on HYVET, a double-blind RCT of 3,845 hypertensive patients 80 years of age or older (Beckett et al. 2008).
Stepped-care therapy began with indapamide with addition of perindopril as needed. At 2 years, the trial was halted because active treatment, as compared with placebo, was associated with a 21 % reduction in the relative risk of death from any cause, a 64 % reduction in the relative risk of heart failure, and a 30 % reduction in the relative risk of stroke (Beckett et al. 2008).
Small dose diuretic: indapamide 1.25 mg or chlorthalidone 25 mg, alternate day should suffice in the majority but serum potassium must be maintained > 3.9 mmol/l.
Prospective data suggest that in older men and women, the use of thiazide diuretic agents is associated with a reduction of approximately one-third in the risk of hip fracture.
Selected elderly over age 80 in whom systolic pressure is constantly greater than 170 mmHg (in the absence of pseudohypertension) may require the following:
in the presence of coronary artery disease, heart failure in past, atrial fibrillation, palpitations (premature beats) or renal dysfunction, TIA or post stroke; a small dose of a beta-blocking drug [nebivolol 2.5 mg. bisoprolol 2.5 to maximum 5 mg once daily; is strongly advisable; the widely used atenolol is not recommended. In SHEP (65–85 year old) a beta-blocker was added to diuretic with salutary results.
Clinicians worldwide should not be reluctant to add a small dose of an appropriate beta-blocker to small dose diuretic in the elderly. The notion that beta-blockers are not effective or harmful or cause genuine diabetes is false. Nonetheless this is a notion held by many experts who write guidelines (UK and USA).
A small dose of a beta-blocking drug, e.g., bisoprolol 2.5–5 mg (not atenolol), is successfully administered for the commonly occurring atrial fibrillation of the elderly or for angina or post-MI and should be just as safe for the elderly hypertensive whose blood pressure must not be aggressively lowered by an ACE inhibitor or calcium antagonist resulting in falls. Amlodipine 2.5 mg or ramipril added to the beta-blocker often suffices. Diuretics are effective in the elderly and with beta-blockers should be preferred therapy because they do not result in falls compared with ACE inhibitor or calcium antagonist therapy. But some individuals older than age 75, particularly women, may be bothered by frequency of micturition.
Thus some may be controlled with 5 mg of bisoprolol only. ACE inhibitors are contraindicated in patients with anemia, a not uncommon finding in the elderly. Much thought must be given in writing the final prescription.
Failure to maintain BP < 150 mmHg may require amlodipine 2.5 to maximum 5 mg daily. Avoid diltiazem and verapamil in elderly because of bothersome constipation and increased HF rate.
Goal BP 130–150 mm in patients age >75 if HF and renal failure are not present. Falls are not infrequent in the elderly who are overtreated with calcium antagonists and ACE inhibitors.
An RCT with nisoldipine in patients with hypertension and non-insulin-dependent diabetes was terminated early because nisoldipine-treated patients had a higher risk of fatal and nonfatal acute MI than observed in the enalapril group: 25/235 versus 5/235 (p < 0.001).
sustained-release calcium antagonists may increase the risk of cardiac mortality in patients who are at risk of IHD events, particularly in those with diabetes, dyslipidemia, and coexisting IHD and in the elderly with silent ischemia or undetected IHD. Long-term RCTs in the elderly age of 75–84 are necessary before calcium antagonists may be considered safe alternatives to diuretics and beta-blockers.
Beta-blockers: The Swedish STOP 2 study (1999) in the elderly showed a significant reduction in mortality and strokes as a result of beta-blocker therapy. Newer agents were not superior to beta-blockers or diuretics. The beta-blockers used were atenolol (a poorly effective beta-blocker) and the non-cardioprotective pindolol.
Some RCTs used propranolol, a beta-blocker influenced unfavorably by cigarette smoking. Smoking interferes with hepatic metabolism of propranolol and decreases blood levels of this agent (Materson et al. 1988). In the Beta-Blocker Heart Attack Trial (BHAT 1982), propranolol failed to prevent fatal and nonfatal MI in smokers but mortality and recurrent MI were significantly improved in nonsmokers.
Propranolol and oxprenolol lose their effects in smokers;
Timolol (Norwegian Multicentre Study Group 1981) have been shown to prevent fatal MI, nonfatal MI, and sudden cardiac death in smokers and nonsmokers. A remarkable 67 % reduction in sudden deaths was recorded in the well-run RCT.
Yet this beta-blocker which caused an outstanding reduction in sudden death not matched by any other cardiac drug is rarely prescribed. A long acting formulation should be developed.
It is clear that beta-blockers are not all alike with regard to their salutary effects, and older agents including atenolol should become obsolete (Khan 2011, 2007a); use in clinical trials should be curtailed (Khan 2003a) and trials in which this drug has been administered should be suspected
The reason why atenolol became the most widely prescribed beta-blocking drug is twofold
1.
It was one of the first agents available following the breakthrough good news provided by propranolol in 1970, and was used by the author.
2.
The drug was observed to have less adverse effects because it achieves a much lower brain concentration than propranolol and metoprolol. But, the beneficial effect depends on the brain concentration and this renders it much less effective, a fact that appears to have eluded teaching professors, clinical Trialist and guideline providers.
In addition, the physician must be aware of the reasons for poor drug control of BP in the treated patient (Table 8-4).
Table 8-4
Reasons for poor drug control of blood pressure
• Poor compliance |
Inconvenient drug dosing, e.g., b.i.d. or t.i.d. |
Inability to purchase drug (financial) |
Adverse effect of drug |
• Related to drug |
Inappropriate drug selection or drug combination |
Interactions with NSAIDs, nasal decongestants, cocaine |
• Salt intake; volume overload |
Diuretic required |
↑Na+ intake |
Renal failure |
• Weight gain |
• Alcohol intake >4 oz/day |
• Renovascular hypertension |
• Other causes of secondary hypertension |
• Cuff size |
• White coat syndrome |
• Pseudohypertension |
• Primary hyperaldosteronism; see section “Resistant Hypertension” |
RCTs of ACE inhibitors have not shown these drugs to be superior to beta-blockers or diuretics (Casas et al. 2005). Importantly, RCTs have indicated that ACE inhibitors rarely achieve goal BP without the addition of a diuretic. In the large PROGRESS (2001) trial, only 42 % achieved goal BP; 58 % required addition of diuretics to achieve control in ~ 66 %.
Therapy for Patients with Coexisting Diseases
In the presence of coexisting disease and target organ damage with comorbid conditions (see Table 8-1), agents are recommended as follows:
Angina, after MI, or suspected IHD: Beta-blockers are strongly recommended. Use diltiazem sustained-release preparation (e.g., or amlodipine if beta-blockers are contraindicated. A DHP used without a beta-blocker may increase mortality if unstable angina or acute MI supervenes.
Atrial fibrillation or other arrhythmias: Beta-blockers are strongly advisable. Hypertension is the leading cause of atrial fibrillation and HF (see Fig. 8-1).
Aortic and other aneurysms: Beta-blockers are strongly indicated because they decrease ejection velocity and shearing stress in arteries; thus, they may provide some protection from rupture or further expansion of the aneurysm.
In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT 2002), diuretics were as effective as ACE inhibitors and calcium antagonists in decreasing CVD outcome.
Diabetic patients have a high incidence of MI and cardiac death; thus, both ACE inhibitors and beta-blockers are strongly recommended. The UKPDS study (1998) showed beta-blocker therapy to be as effective as captopril in reducing the risk of macrovascular and microvascular complications in type 2 diabetes . Importantly, glycemic control was not different between groups.
Stroke or transient ischemic attack: BP must be cautiously reduced, if at all, in the acute stage. A beta-blocker or diuretic or combination is advisable.
In the large PROGRESS (2001) RCT 6,105 patients with previous stroke or transient ischemic attack showed no reduction in the risk of cardiovascular events or stroke, but the combination with indapamide significantly reduced adverse events.
In the large Captopril Prevention Project (CAPP 1999) study of captopril versus diuretic and beta-blocker, fatal and nonfatal stroke was increased in the captopril group ( p = 0.044), with no significant differences in other events. Primary endpoint events occurred in 363 patients in the captopril group and 335 in the conventional-treatment group p=0·52). Cardiovascular mortality was not significantly lower with captopril than with conventional treatment (76 vs 95 events; p=0·092), the rate of fatal and non-fatal MI was similar (162 vs 161), in addition, some captopril-treated patients required addition of diuretic to achieve goal BP.
Alpha-blockers may increase cardiovascular mortality and have not been shown to prevent or reduce LVH. Patients with dyslipidemia are at high risk of IHD events. Beta-blockers are the logical choice. If beta-blockers are contraindicated, an ACE inhibitor and low-dose diuretic are advisable.
Congestive heart failure (CHF) classes I–II and III: Diuretics plus ACE inhibitor plus a beta-blocker. In this subset, beta-blockers have been shown in RCTs to prolong life and to reduce the risk of hospitalization.
Thus, beta-blockers are strongly indicated for patients with LV dysfunction, ejection fraction 25–45 %. The combination of bisoprolol ,carvedilol or nebivolol and an ACE inhibitor is advisable.
Renal insufficiency, except renovascular hypertension, creatinine clearance <265 μmol/L, 3 mg/dL: ACE inhibitor plus loop diuretic is indicated, but a beta-blocker and/or calcium antagonist may be necessary to achieve goal BP; see later discussion of metolazone.
LVH: Beta-blockers and/or ACE inhibitors are preferred. Avoid alpha-blockers. Calcium antagonists and alpha-blockers have not shown to reduce LV mass consistently (Devereux 1985; Dunn et al. 1987 ).
Liver disease: Avoid methyldopa and labetalol; the latter may cause hepatic necrosis (Clark et al. 1990).
Severe depression: Diuretics or ACE inhibitors are recommended; a calcium antagonist may be used in the absence of diabetes. Beta-blockers may increase depression, but this effect is rare and does not contraindicate the use of beta-blocker therapy if needed. Reserpine, methyldopa, clonidine, and other central alpha-agonists are contraindicated.
Stasis edema or varicose veins with edema: Avoid calcium antagonists, particularly the DHPs.
Renal vascular hypertension or anemia: Avoid ACE inhibitors and ARBs.
Gastroreflux syndrome: Avoid calcium antagonists because they may increase reflux.
Gout: Avoid diuretics.
Sensitivity to sulfonamides: Avoid all diuretics except ethacrynic acid and amiloride.
Severe peripheral vascular disease: Avoid beta-blockers; these agents are not contraindicated in patients with mild or stable peripheral vascular disease because these patients often have coexisting IHD, and beta-blockers may ameliorate symptoms and prolong life in this subset.
Renal calculi: Avoid triamterene because this agent may precipitate calculi (see Chap. 7).< div class='tao-gold-member'>Only gold members can continue reading. Log In or Register to continue
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