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What we really need to do to reduce cardiovascular events in hypertensive patients
- In your efforts to reduce cardiovascular events in hypertensive patients, concentrate on getting patients to goal, rather than on which drugs to use to get them there (A).
- Beta-blockers—especially atenolol—should not be the drug of first choice when treating older patients with hypertension (A).
- Multiple drugs are required for adequate blood pressure control in most patients (A).
Strength of recommendation (SOR)
- Good quality patient-oriented evidence
- Inconsistent or limited-quality patient-oriented evidence
- Consensus, usual practice, opinion, disease-oriented evidence, case series
Forget about a silver bullet.
Researchers have conducted numerous trials over the last decade to find an antihypertensive drug that best reduces cardiovascular events while reducing blood pressure. However, this objective review of 13 comparative antihypertensive drug trials over the past decade involving more than 168,000 patients reveals no great differences in the cardiovascular protective effects of diuretics, beta-blockers, calcium channel blockers, angiotensin receptor blockers (ARBs), and angiotensin-converting enzyme (ACE) inhibitors.
In fact, this review indicates that there were no significant differences in the primary cardiovascular endpoints in more than 90% of the patients studied. Where a difference in secondary clinical outcome was demonstrated, fewer events consistently occurred in the regimen that reached the lower blood pressure level.
This assessment will likely fly in the face of the way that many would view this body of research. That’s understandable. At first glance, it would appear that these 13 trials, with different methodology and endpoints, have produced conflicting conclusions with the confusion worsened by pharmaceutical companies seeking to interpret the results to best suit their marketing needs.1-3
It is not the quality of the data, however, that is in question; the controversy lies in the interpretation. Subjecting the studies to further statistical analysis would simply obscure the information.
By reviewing the data impartially and objectively as a whole, though, and interpreting individual studies in light of similar studies, it becomes evident that there is more consensus than conflict. The studies support the notion that we should concentrate on getting patients to goal, rather than focusing on which drugs we’ll use to get them there.
Methods
I performed a PubMed search of the last 10 years using the keywords hypertension, comparative, drug trials. I supplemented my search with references from the JNC 7, WHO, BHS/NICE, and European hypertension guidelines. For this review, I included only randomized controlled trials with clinical cardiovascular primary endpoints. The studies had to have enrolled at least 500 patients and followed them for at least 3 years. Thirteen trials satisfied these criteria.4-17 All 13 are summarized in the TABLE, but I will review 5 of the more recent trials here. They are:
- ASCOT-BPLA—Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm
- ALLHAT—Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial
- ANBP2—Second Australian National Blood Pressure Study
- LIFE—Losartan Intervention For Endpoint reduction
- VALUE—Valsartan Antihypertensive Long-term Use Evaluation.
Calcium channel blockers vs beta-blockers
ASCOT-BPLA studied 19,257 high-risk hypertensive patients on amlodipine (Norvasc), adding perindopril, or atenolol (Tenormin), adding bendroflumethiazide.17 After 5.5 years, the primary end-point of nonfatal myocardial infarction (MI) and cardiovascular death was similar (relative risk [RR]=0.90; 95% confidence interval [CI], 0.79–1.02; P=.1052).
Total coronary endpoint, stroke, and mortality were all lower on amlodipine. Blood pressure was significantly lower on amlodipine compared with atenolol, with an average difference of 2.7/1.9 mm Hg over the trial duration.18
At the end of the trial, patients on amlodipine also had a significantly higher HDL cholesterol, and lower body mass index, triglyceride, creatinine, and glucose levels. However, when researchers made a multivariate adjustment for all of these risk factors, cardiovascular event rate differences between the 2 groups disappeared, underscoring the importance of controlling for all risk factors in reducing clinical cardiovascular events.18,19
A careful reading of ASCOT-BPLA, then, makes it clear that this study does not support the notion that newer antihypertensives (calcium channel blockers and ACE inhibitors) are superior to older ones (beta-blockers and diuretics).20,21 This study actually demonstrates that while blood pressure reduction is vital, the differences between regimens are less important.
TABLE
More consensus than conflict among 13 comparative antihypertensive drug trials with cardiovascular primary endpoints
| YEAR | TRIAL | N | DRUGS COMPARED | PRIMARY ENDPOINT | RELATIVE RISK (95% CI) | P VALUE |
|---|---|---|---|---|---|---|
| 1998 | UKPDS4 | 758 | Captopril vs atenolol | Clinical diabetic event | 1.1 (0.86–1.41) | .43 |
| Diabetic death | 1.27 (0.82–1.97) | .28 | ||||
| Total mortality | 1.14 (0.81–1.61) | .44 | ||||
| 1999 | CAPPP5 | 10,985 | Captopril vs diuretic/beta-blocker | MI+stroke+CV death | 1.05 (0.90–1.22) | .52 |
| 1999 | STOP 26 | 6614 | New vs conventional drugs | CV death | 0.99 (0.84–1.16) | .89 |
| 4418 | ACE I vs conventional drugs | CV death | 1.01 (0.84–1.22) | .89 | ||
| 4409 | CCB vs conventional drugs | CV death | 0.97 (0.80–1.17) | .72 | ||
| 2000 | INSIGHT7 | 6321 | Nifedipine LA vs diuretic | CV death, MI, HF, stroke | 1.1 (0.91–1.34) | .35 |
| 2000 | NORDIL8 | 10,881 | Diltiazem vs beta-blocker/diuretic | Stroke, MI, CV death | 1.00 (0.87–1.15) | .97 |
| 2002 | LIFE9 | 9193 | Losartan vs atenolol | CV death, stroke, MI | 0.87 (0.77–0.98) | .021 |
| 2002–3 | ALLHAT10,11 | 24,303 | Amlodipine vs chlorthalidone | Fatal CHD, nonfatal MI | 0.98 (0.90–1.07) | .65 |
| 24,309 | Lisinopril vs chlorthalidone | Fatal CHD, nonfatal MI | 0.99 (0.91–1.08) | .81 | ||
| 24,314 | Doxazosin vs chlorthalidone | Fatal CHD, nonfatal MI | 1.03 (0.93–1.15) | .62 | ||
| 2003 | ANBP212 | 6083 | ACE I vs diuretic | CV event,* death | 0.89 (0.79–1.00) | .05 |
| 2003 | CONVINCE13 | 16,602 | Verapamil vs atenolol/thiazide | Stroke, MI, CV death | 1.02 (0.88–1.18) | .77 |
| 2003 | INVEST14 | 22,576 | Verapamil vs atenolol | Death, nonfatal MI, nonfatal stroke | 0.98 (0.90–1.06) | .57 |
| 2004 | VALUE15 | 15,245 | Valsartan vs amlodipine | CV event† | 1.04 (0.94–1.15) | .49 |
| 2004 | JMIC-B16 | 1650 | Nifedipine retard vs ACE I | Cardiac events‡ | 1.05 (0.81–1.37) | .86 |
| 2005 | ASCOT17 | 19,257 | Amlodipine (+ perindopril) vs atenolol (+ thiazide) | Nonfatal MI, fatal CHD | 0.90 (0.79–1.02) | .1052 |
| ACE I, angiotensin-converting enzyme inhibitor; CCB, calcium channel blocker; CHD, coronary heart disease; CI, confidence interval; CV, cardiovascular; HF, heart failure; MI, myocardial infarction. | ||||||
| *Defined as coronary events including MI, heart failure, acute occlusion of artery, dissecting or ruptured aortic aneurysm, and cerebrovascular events including stroke and transient ischemic attacks. | ||||||
| † Defined as cardiac death, hospitalized heart failure, nonfatal MI, and emergency procedures to prevent MI. | ||||||
| ‡ Defined as cardiac death or sudden death, MI, angina pectoris requiring hospitalization, heart failure requiring hospitalization, serious arrhythmia, and coronary interventions. | ||||||
Largest hypertensive trial ever studied 4 drugs
ALLHAT, the largest hypertensive trial ever conducted, randomized 15,255 patients to chlorthalidone, 9061 to doxazosin (Cardura), 9048 to amlodipine, and 9054 to lisinopril (Prinivil/Zestril).10,11 (The arm involving doxazosin was terminated after 3.2 years.11,22)
Compared with the beta-blocker, more patients achieved target blood pressure control on chlorthalidone (63% vs 58%), and systolic blood pressure was about 2 mm Hg lower. Although the primary outcome of fatal coronary heart disease and nonfatal MI was equal in both groups (doxazosin=7.91%; chlorthalidone=7.76%; RR=1.03 [95% CI, 0.93–1.15]; P=.62), the doxazosin arm had more stroke, heart failure, and combined cardiovascular events.
Patients on amlodipine and lisinopril had a longer follow-up of 4.9 years. Systolic blood pressure was higher on amlodipine (0.8 mm Hg, P=.03) and lisinopril (2 mm Hg, P<.001) than on chlorthalidone. The primary endpoint (fatal coronary heart disease and nonfatal MI) was similar on the diuretic (11.5%), calcium channel blocker (11.3%; RR=0.98 [95% CI, 0.90–1.07]; P=.65), and ACE inhibitor (11.4%; RR=0.99 [95% CI, 0.91–1.08]; P=.81).
Compared with the diuretic arm, the calcium channel blocker arm had a higher incidence of heart failure, while the ACE inhibitor arm had a higher incidence of heart failure, stroke, and combined cardiovascular disease. The results were similar whatever the initial glycemic state, renal function status, and racial makeup of the patients studied.23-26 More than 60% of patients in ALLHAT required 2 or more drugs for good blood pressure control.27
“Diuretics first” for patients with or without diabetes?
In ALLHAT, although diabetes occurred more frequently and fasting glucose rose in patients on diuretics, these metabolic abnormalities did not result in more cardiovascular events. Even among patients with diabetes, heart failure was more common on doxazosin, amlodipine, and lisinopril compared with those on chlorthalidone.23,24
Given that the ultimate aim of hypertensive therapy is to reduce clinical disease—not just to improve laboratory profiles—ALLHAT should put to rest any apprehension physicians have about diuretic use. These findings have even led to suggestions that diuretics be the first line antihypertensive agent, in both diabetic and nondiabetic patients.28-30
ACE inhibitor vs diuretic
ANBP2 randomized hypertensive patients to initial treatment with an ACE inhibitor (n=3044) or a diuretic (n=3039).12 With similar blood pressure reduction in both arms (26/12 mm Hg), treatment with the ACE inhibitor resulted in a lower incidence of the composite primary end-point of cardiovascular events or total death that was of borderline significance (ACE inhibitor=22.8%; diuretic=24.2%; RR=0.89 [95% CI, 0.79–1.00]; P=.05).
Among women, there was no difference between the ACE inhibitor and diuretic groups. In the overall population, there was also no difference individually of total mortality or incidence of first cardiovascular event or death.
Thus ANBP2 actually confirms the results from ALLHAT by showing that ACE inhibitors and diuretics are equivalent in reducing cardiovascular events in hypertension.31
Losartan vs atenolol
In the LIFE study, 9193 hypertensive patients with left ventricular hypertrophy were randomized to either losartan (Cozaar) or atenolol.9 Losartan treatment resulted in a marked reduction in stroke incidence, which produced a significant reduction in the composite primary end-point of death, MI, or stroke (11% vs 13%; RR=0.87 [95% CI, 0.77–0.98]; P=.021).
When only the 1195 patients with diabetes were assessed, there was a significant reduction not only in the primary endpoint but also in cardiovascular and total mortality.32 Surprisingly, the reduction of stroke incidence did not reach statistical significance in this diabetic population (RR=0.79 [95% CI, 0.55–1.14]; P=.204).
A word of caution, though: The results of LIFE should be taken together with data from other trials. No other study has demonstrated a special benefit from the renin-angiotensin antagonists in preventing stroke. In fact, ACE inhibitors were weaker than the comparator drugs in preventing stroke in both CAPPP (TABLE) and ALLHAT.5,10 Various reviews have suggested that among antihypertensive drugs, it is the diuretics and calcium channel blockers that may be more useful in stroke reduction.33,34
Chalk the benefit up to the drop in blood pressure
In the LIFE study, the treated mean systolic blood pressure was lower with losartan in the overall (1.1 mm Hg; P=.017) and diabetic (2 mm Hg; P value not stated) populations, and thus the clinical benefit could possibly have been from the better blood pressure reduction on losartan. Furthermore, there is evidence that beta-blockers are less useful in the older hypertensive patient, and are especially weak in preventing stroke incidence.35,36
Rather than showing the superiority of the ARB, it is fair to say that LIFE actually confirms the importance of blood pressure reduction, and reveals the weaker cardiovascular protective effect of atenolol in older hypertensive patients.
Valsartan, amlodipine in high-risk patients
VALUE randomized 15,245 high-risk hypertensive patients to valsartan (Diovan) and amlodipine.15,37 Trial researchers sought to study the difference—for the same level of blood pressure reduction—between the 2 regimens in the incidence of cardiac events defined as sudden cardiac death, hospitalized heart failure, nonfatal MI, and emergency procedures to prevent MI. That said, the attained blood pressure was lower on the calcium channel blocker: 4.0/2.1 mm Hg at 1 month and 2.1/1.7 mm Hg at the end of study.
After 4.2 years, there was no significant difference in the primary endpoint of first cardiac event (10.6% valsartan/10.4% amlodipine; RR=1.04 [95% CI, 0.94–1.15]; P=.49). Diabetes was lower, but the rate of MI was higher on valsartan. After correction for the blood pressure difference, the composite of cardiac events, stroke, death, or MI was similar in the 2 groups.38
VALUE patients reaching adequate blood pressure control by 6 months fared better, regardless of drug type used. Thus demonstrating that the benefit from good blood pressure control was more important than the subtle differences between antihypertensive drugs. The better metabolic profile in the angiotensin receptor blocker arm did not translate into a reduction in adverse clinical disease.
The VALUE trial suggests (as did ALLHAT) that drugs targeting the reninangiotensin system do not provide special cardiovascular protection.10,15
Choosing an antihypertensive drug according to the clinical disease and target organ most at risk of damage is logical and in keeping with numerous guidelines.42-45 Thus, you’ll want to treat hypertensive patients with these conditions as follows:
- Angina pectoris. Therapy should include a beta-blocker or calcium channel blocker, given their definite antianginal and possible anti-atherosclerotic effects.16,46,47
- Prior MI. Start the patient on a beta-blocker.47
- Poor left ventricular function. Start the patient on a diuretic, and then add an ACE inhibitor and beta-blocker, as needed.10,49,50
- Prior stroke (or a patient at special risk of stroke). Begin therapy with a calcium channel blocker or a diuretic.33,34
- Diabetic proteinuria. An ARB or an ACE inhibitor is best suited to prevent and delay nephropathy.51-54
Consensus emerges from studies spanning 10 years
This objective review of the comparative hypertension drug trials shows that there are no great differences in the cardiovascular protective efficacy of the diuretics, beta-blockers, calcium channel blockers, ARBs, and ACE inhibitors.
There was no significant difference in the cardiovascular primary endpoint in 11 of the 13 trials reviewed, involving 91% of the randomized 168,593 patients (TABLE).4-8,10,11,13-17 Of the remaining 2 trials, the difference in ANBP2 just reached a P value of .05, while the result in LIFE was driven by a lower stroke incidence on ARB treatment that is not noted in any of the other studies involving an ARB or ACE inhibitor.4-6,10,12-15
Focus on controlling blood pressure with combination of drugs
Given the very large number of patients studied in these well-conducted trials, if there were any especially useful, or detrimental, cardiovascular effect of a particular class of antihypertensive drug, it would have been obvious by now. Since most patients will require multiple drugs, the equivalent protective efficacy of different antihypertensive drugs is reassuring and suggests that physicians should not worry too much about which drug to start the patient on.28 Rather, the emphasis should be on how best to reach adequate blood pressure control by combining several antihypertensive drugs.
Small blood pressure differences, big impact
In LIFE (losartan vs atenolol), ALLHAT (doxazosin, amlodipine, lisinopril vs chlorthalidone), VALUE (amlodipine vs valsartan), and ASCOT (amlodipine vs atenolol), where a secondary cardiovascular endpoint was lower in one of the treatment arms, it was always the arm with the lower achieved blood pressure that had the better clinical outcome.9-11,15,17
Marya Ostrowski, JFP Editor
With only 50% of patients typically taking their medications as prescribed and the cost of poor adherence reaching an estimated $177 billion annually in direct and indirect health care costs, one medication safety group is saying enough is enough.
The National Council on Patient Information and Education (NCPIE), a nonprofit coalition that includes health professional associations, government agencies, and pharmaceutical companies, issued a report this summer detailing a 10-step action plan for reducing the adverse health and economic consequences of poor medication adherence.
The plan, developed by a panel of experts that NCPIE convened, calls on the government and health care community to, among other things:
- address the barriers to patient adherence for patients with low health literacy.
- develop a curriculum on medication adherence for use in medical schools.
- mount a unified national education campaign to make patient adherence a national health priority.
“Medication adherence is America’s new drug problem,” said Carolyn M. Clancy, MD, director of the Agency for Healthcare Research and Quality. AHRQ has been working with NCPIE, the FDA, and the National Consumers League to develop a public education campaign on medication adherence, according to Clancy. The NCPIE report helps to bolster those ongoing efforts, she said.
On the heels of the report, NCPIE is planning on releasing videos that will teach seniors about properly taking their medications, according to Ray Bullman, NCPIE’s executive vice president.
To learn more about NCPIE’s initiatives, or for a copy of the report, Enhancing Prescription Medicine Adherence: A National Action Plan, point your browser to: www.talkaboutrx.org.
These achieved blood pressure differences although small, were significant. Small overall mean blood pressure differences could mask much larger blood pressure differences in the individual patient. Consider, for instance, the HOPE (Heart Outcomes Prevention Evaluation) trial, where a reported overall blood pressure difference of only 3/1 mm Hg between the 2 treatment arms masked a difference of 10/4 mm Hg in 24-hour ambulatory blood pressure and a difference of 17/8 mm Hg in night-time blood pressure.39,40
Thus, instead of trying to work out why antihypertensive drugs could exert apparently different cardiovascular protective efficacy in different trials, the simple and consistent message is that the lower the achieved blood pressure, the lower the adverse clinical cardiovascular outcome.
What makes sense for your patient?
In selecting antihypertensive drugs, physicians should be guided by data supporting a particular drug in coexisting clinical conditions. (See “Where to begin when there are coexisting conditions,”.) In the hypertensive patient who is free of clinical disease, a case can be made for a diuretic as the first-line drug, although calcium channel blockers, ARBs, and ACE inhibitors can also claim evidence to support their use. In the older patient, beta-blockers—especially atenolol—should not be the drug of first choice.35,36,41
As this review of comparative hypertension drug trials shows, multiple drugs are required for adequate blood pressure control in most patients. Thus, physicians should not be too preoccupied about how to initiate treatment, but remember to add drugs until adequate control is achieved.
Correspondence
H T Ong, FRCP, FACC, FESC, H T Ong Heart Clinic, 251C Burma Road, Penang 10350, Malaysia; [email protected]
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52. Parving HH, Lehnert H, Mortensen JB, et al. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001;345:870-878.
53. Brenner BM, Cooper ME, Zeeuw D de, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345:861-869.
54. Wright JT, Bakris G, Greene T, et al. For the African American Study of Kidney Disease and Hypertension Study Group. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. JAMA 2002;288:2421-2431.
- In your efforts to reduce cardiovascular events in hypertensive patients, concentrate on getting patients to goal, rather than on which drugs to use to get them there (A).
- Beta-blockers—especially atenolol—should not be the drug of first choice when treating older patients with hypertension (A).
- Multiple drugs are required for adequate blood pressure control in most patients (A).
Strength of recommendation (SOR)
- Good quality patient-oriented evidence
- Inconsistent or limited-quality patient-oriented evidence
- Consensus, usual practice, opinion, disease-oriented evidence, case series
Forget about a silver bullet.
Researchers have conducted numerous trials over the last decade to find an antihypertensive drug that best reduces cardiovascular events while reducing blood pressure. However, this objective review of 13 comparative antihypertensive drug trials over the past decade involving more than 168,000 patients reveals no great differences in the cardiovascular protective effects of diuretics, beta-blockers, calcium channel blockers, angiotensin receptor blockers (ARBs), and angiotensin-converting enzyme (ACE) inhibitors.
In fact, this review indicates that there were no significant differences in the primary cardiovascular endpoints in more than 90% of the patients studied. Where a difference in secondary clinical outcome was demonstrated, fewer events consistently occurred in the regimen that reached the lower blood pressure level.
This assessment will likely fly in the face of the way that many would view this body of research. That’s understandable. At first glance, it would appear that these 13 trials, with different methodology and endpoints, have produced conflicting conclusions with the confusion worsened by pharmaceutical companies seeking to interpret the results to best suit their marketing needs.1-3
It is not the quality of the data, however, that is in question; the controversy lies in the interpretation. Subjecting the studies to further statistical analysis would simply obscure the information.
By reviewing the data impartially and objectively as a whole, though, and interpreting individual studies in light of similar studies, it becomes evident that there is more consensus than conflict. The studies support the notion that we should concentrate on getting patients to goal, rather than focusing on which drugs we’ll use to get them there.
Methods
I performed a PubMed search of the last 10 years using the keywords hypertension, comparative, drug trials. I supplemented my search with references from the JNC 7, WHO, BHS/NICE, and European hypertension guidelines. For this review, I included only randomized controlled trials with clinical cardiovascular primary endpoints. The studies had to have enrolled at least 500 patients and followed them for at least 3 years. Thirteen trials satisfied these criteria.4-17 All 13 are summarized in the TABLE, but I will review 5 of the more recent trials here. They are:
- ASCOT-BPLA—Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm
- ALLHAT—Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial
- ANBP2—Second Australian National Blood Pressure Study
- LIFE—Losartan Intervention For Endpoint reduction
- VALUE—Valsartan Antihypertensive Long-term Use Evaluation.
Calcium channel blockers vs beta-blockers
ASCOT-BPLA studied 19,257 high-risk hypertensive patients on amlodipine (Norvasc), adding perindopril, or atenolol (Tenormin), adding bendroflumethiazide.17 After 5.5 years, the primary end-point of nonfatal myocardial infarction (MI) and cardiovascular death was similar (relative risk [RR]=0.90; 95% confidence interval [CI], 0.79–1.02; P=.1052).
Total coronary endpoint, stroke, and mortality were all lower on amlodipine. Blood pressure was significantly lower on amlodipine compared with atenolol, with an average difference of 2.7/1.9 mm Hg over the trial duration.18
At the end of the trial, patients on amlodipine also had a significantly higher HDL cholesterol, and lower body mass index, triglyceride, creatinine, and glucose levels. However, when researchers made a multivariate adjustment for all of these risk factors, cardiovascular event rate differences between the 2 groups disappeared, underscoring the importance of controlling for all risk factors in reducing clinical cardiovascular events.18,19
A careful reading of ASCOT-BPLA, then, makes it clear that this study does not support the notion that newer antihypertensives (calcium channel blockers and ACE inhibitors) are superior to older ones (beta-blockers and diuretics).20,21 This study actually demonstrates that while blood pressure reduction is vital, the differences between regimens are less important.
TABLE
More consensus than conflict among 13 comparative antihypertensive drug trials with cardiovascular primary endpoints
| YEAR | TRIAL | N | DRUGS COMPARED | PRIMARY ENDPOINT | RELATIVE RISK (95% CI) | P VALUE |
|---|---|---|---|---|---|---|
| 1998 | UKPDS4 | 758 | Captopril vs atenolol | Clinical diabetic event | 1.1 (0.86–1.41) | .43 |
| Diabetic death | 1.27 (0.82–1.97) | .28 | ||||
| Total mortality | 1.14 (0.81–1.61) | .44 | ||||
| 1999 | CAPPP5 | 10,985 | Captopril vs diuretic/beta-blocker | MI+stroke+CV death | 1.05 (0.90–1.22) | .52 |
| 1999 | STOP 26 | 6614 | New vs conventional drugs | CV death | 0.99 (0.84–1.16) | .89 |
| 4418 | ACE I vs conventional drugs | CV death | 1.01 (0.84–1.22) | .89 | ||
| 4409 | CCB vs conventional drugs | CV death | 0.97 (0.80–1.17) | .72 | ||
| 2000 | INSIGHT7 | 6321 | Nifedipine LA vs diuretic | CV death, MI, HF, stroke | 1.1 (0.91–1.34) | .35 |
| 2000 | NORDIL8 | 10,881 | Diltiazem vs beta-blocker/diuretic | Stroke, MI, CV death | 1.00 (0.87–1.15) | .97 |
| 2002 | LIFE9 | 9193 | Losartan vs atenolol | CV death, stroke, MI | 0.87 (0.77–0.98) | .021 |
| 2002–3 | ALLHAT10,11 | 24,303 | Amlodipine vs chlorthalidone | Fatal CHD, nonfatal MI | 0.98 (0.90–1.07) | .65 |
| 24,309 | Lisinopril vs chlorthalidone | Fatal CHD, nonfatal MI | 0.99 (0.91–1.08) | .81 | ||
| 24,314 | Doxazosin vs chlorthalidone | Fatal CHD, nonfatal MI | 1.03 (0.93–1.15) | .62 | ||
| 2003 | ANBP212 | 6083 | ACE I vs diuretic | CV event,* death | 0.89 (0.79–1.00) | .05 |
| 2003 | CONVINCE13 | 16,602 | Verapamil vs atenolol/thiazide | Stroke, MI, CV death | 1.02 (0.88–1.18) | .77 |
| 2003 | INVEST14 | 22,576 | Verapamil vs atenolol | Death, nonfatal MI, nonfatal stroke | 0.98 (0.90–1.06) | .57 |
| 2004 | VALUE15 | 15,245 | Valsartan vs amlodipine | CV event† | 1.04 (0.94–1.15) | .49 |
| 2004 | JMIC-B16 | 1650 | Nifedipine retard vs ACE I | Cardiac events‡ | 1.05 (0.81–1.37) | .86 |
| 2005 | ASCOT17 | 19,257 | Amlodipine (+ perindopril) vs atenolol (+ thiazide) | Nonfatal MI, fatal CHD | 0.90 (0.79–1.02) | .1052 |
| ACE I, angiotensin-converting enzyme inhibitor; CCB, calcium channel blocker; CHD, coronary heart disease; CI, confidence interval; CV, cardiovascular; HF, heart failure; MI, myocardial infarction. | ||||||
| *Defined as coronary events including MI, heart failure, acute occlusion of artery, dissecting or ruptured aortic aneurysm, and cerebrovascular events including stroke and transient ischemic attacks. | ||||||
| † Defined as cardiac death, hospitalized heart failure, nonfatal MI, and emergency procedures to prevent MI. | ||||||
| ‡ Defined as cardiac death or sudden death, MI, angina pectoris requiring hospitalization, heart failure requiring hospitalization, serious arrhythmia, and coronary interventions. | ||||||
Largest hypertensive trial ever studied 4 drugs
ALLHAT, the largest hypertensive trial ever conducted, randomized 15,255 patients to chlorthalidone, 9061 to doxazosin (Cardura), 9048 to amlodipine, and 9054 to lisinopril (Prinivil/Zestril).10,11 (The arm involving doxazosin was terminated after 3.2 years.11,22)
Compared with the beta-blocker, more patients achieved target blood pressure control on chlorthalidone (63% vs 58%), and systolic blood pressure was about 2 mm Hg lower. Although the primary outcome of fatal coronary heart disease and nonfatal MI was equal in both groups (doxazosin=7.91%; chlorthalidone=7.76%; RR=1.03 [95% CI, 0.93–1.15]; P=.62), the doxazosin arm had more stroke, heart failure, and combined cardiovascular events.
Patients on amlodipine and lisinopril had a longer follow-up of 4.9 years. Systolic blood pressure was higher on amlodipine (0.8 mm Hg, P=.03) and lisinopril (2 mm Hg, P<.001) than on chlorthalidone. The primary endpoint (fatal coronary heart disease and nonfatal MI) was similar on the diuretic (11.5%), calcium channel blocker (11.3%; RR=0.98 [95% CI, 0.90–1.07]; P=.65), and ACE inhibitor (11.4%; RR=0.99 [95% CI, 0.91–1.08]; P=.81).
Compared with the diuretic arm, the calcium channel blocker arm had a higher incidence of heart failure, while the ACE inhibitor arm had a higher incidence of heart failure, stroke, and combined cardiovascular disease. The results were similar whatever the initial glycemic state, renal function status, and racial makeup of the patients studied.23-26 More than 60% of patients in ALLHAT required 2 or more drugs for good blood pressure control.27
“Diuretics first” for patients with or without diabetes?
In ALLHAT, although diabetes occurred more frequently and fasting glucose rose in patients on diuretics, these metabolic abnormalities did not result in more cardiovascular events. Even among patients with diabetes, heart failure was more common on doxazosin, amlodipine, and lisinopril compared with those on chlorthalidone.23,24
Given that the ultimate aim of hypertensive therapy is to reduce clinical disease—not just to improve laboratory profiles—ALLHAT should put to rest any apprehension physicians have about diuretic use. These findings have even led to suggestions that diuretics be the first line antihypertensive agent, in both diabetic and nondiabetic patients.28-30
ACE inhibitor vs diuretic
ANBP2 randomized hypertensive patients to initial treatment with an ACE inhibitor (n=3044) or a diuretic (n=3039).12 With similar blood pressure reduction in both arms (26/12 mm Hg), treatment with the ACE inhibitor resulted in a lower incidence of the composite primary end-point of cardiovascular events or total death that was of borderline significance (ACE inhibitor=22.8%; diuretic=24.2%; RR=0.89 [95% CI, 0.79–1.00]; P=.05).
Among women, there was no difference between the ACE inhibitor and diuretic groups. In the overall population, there was also no difference individually of total mortality or incidence of first cardiovascular event or death.
Thus ANBP2 actually confirms the results from ALLHAT by showing that ACE inhibitors and diuretics are equivalent in reducing cardiovascular events in hypertension.31
Losartan vs atenolol
In the LIFE study, 9193 hypertensive patients with left ventricular hypertrophy were randomized to either losartan (Cozaar) or atenolol.9 Losartan treatment resulted in a marked reduction in stroke incidence, which produced a significant reduction in the composite primary end-point of death, MI, or stroke (11% vs 13%; RR=0.87 [95% CI, 0.77–0.98]; P=.021).
When only the 1195 patients with diabetes were assessed, there was a significant reduction not only in the primary endpoint but also in cardiovascular and total mortality.32 Surprisingly, the reduction of stroke incidence did not reach statistical significance in this diabetic population (RR=0.79 [95% CI, 0.55–1.14]; P=.204).
A word of caution, though: The results of LIFE should be taken together with data from other trials. No other study has demonstrated a special benefit from the renin-angiotensin antagonists in preventing stroke. In fact, ACE inhibitors were weaker than the comparator drugs in preventing stroke in both CAPPP (TABLE) and ALLHAT.5,10 Various reviews have suggested that among antihypertensive drugs, it is the diuretics and calcium channel blockers that may be more useful in stroke reduction.33,34
Chalk the benefit up to the drop in blood pressure
In the LIFE study, the treated mean systolic blood pressure was lower with losartan in the overall (1.1 mm Hg; P=.017) and diabetic (2 mm Hg; P value not stated) populations, and thus the clinical benefit could possibly have been from the better blood pressure reduction on losartan. Furthermore, there is evidence that beta-blockers are less useful in the older hypertensive patient, and are especially weak in preventing stroke incidence.35,36
Rather than showing the superiority of the ARB, it is fair to say that LIFE actually confirms the importance of blood pressure reduction, and reveals the weaker cardiovascular protective effect of atenolol in older hypertensive patients.
Valsartan, amlodipine in high-risk patients
VALUE randomized 15,245 high-risk hypertensive patients to valsartan (Diovan) and amlodipine.15,37 Trial researchers sought to study the difference—for the same level of blood pressure reduction—between the 2 regimens in the incidence of cardiac events defined as sudden cardiac death, hospitalized heart failure, nonfatal MI, and emergency procedures to prevent MI. That said, the attained blood pressure was lower on the calcium channel blocker: 4.0/2.1 mm Hg at 1 month and 2.1/1.7 mm Hg at the end of study.
After 4.2 years, there was no significant difference in the primary endpoint of first cardiac event (10.6% valsartan/10.4% amlodipine; RR=1.04 [95% CI, 0.94–1.15]; P=.49). Diabetes was lower, but the rate of MI was higher on valsartan. After correction for the blood pressure difference, the composite of cardiac events, stroke, death, or MI was similar in the 2 groups.38
VALUE patients reaching adequate blood pressure control by 6 months fared better, regardless of drug type used. Thus demonstrating that the benefit from good blood pressure control was more important than the subtle differences between antihypertensive drugs. The better metabolic profile in the angiotensin receptor blocker arm did not translate into a reduction in adverse clinical disease.
The VALUE trial suggests (as did ALLHAT) that drugs targeting the reninangiotensin system do not provide special cardiovascular protection.10,15
Choosing an antihypertensive drug according to the clinical disease and target organ most at risk of damage is logical and in keeping with numerous guidelines.42-45 Thus, you’ll want to treat hypertensive patients with these conditions as follows:
- Angina pectoris. Therapy should include a beta-blocker or calcium channel blocker, given their definite antianginal and possible anti-atherosclerotic effects.16,46,47
- Prior MI. Start the patient on a beta-blocker.47
- Poor left ventricular function. Start the patient on a diuretic, and then add an ACE inhibitor and beta-blocker, as needed.10,49,50
- Prior stroke (or a patient at special risk of stroke). Begin therapy with a calcium channel blocker or a diuretic.33,34
- Diabetic proteinuria. An ARB or an ACE inhibitor is best suited to prevent and delay nephropathy.51-54
Consensus emerges from studies spanning 10 years
This objective review of the comparative hypertension drug trials shows that there are no great differences in the cardiovascular protective efficacy of the diuretics, beta-blockers, calcium channel blockers, ARBs, and ACE inhibitors.
There was no significant difference in the cardiovascular primary endpoint in 11 of the 13 trials reviewed, involving 91% of the randomized 168,593 patients (TABLE).4-8,10,11,13-17 Of the remaining 2 trials, the difference in ANBP2 just reached a P value of .05, while the result in LIFE was driven by a lower stroke incidence on ARB treatment that is not noted in any of the other studies involving an ARB or ACE inhibitor.4-6,10,12-15
Focus on controlling blood pressure with combination of drugs
Given the very large number of patients studied in these well-conducted trials, if there were any especially useful, or detrimental, cardiovascular effect of a particular class of antihypertensive drug, it would have been obvious by now. Since most patients will require multiple drugs, the equivalent protective efficacy of different antihypertensive drugs is reassuring and suggests that physicians should not worry too much about which drug to start the patient on.28 Rather, the emphasis should be on how best to reach adequate blood pressure control by combining several antihypertensive drugs.
Small blood pressure differences, big impact
In LIFE (losartan vs atenolol), ALLHAT (doxazosin, amlodipine, lisinopril vs chlorthalidone), VALUE (amlodipine vs valsartan), and ASCOT (amlodipine vs atenolol), where a secondary cardiovascular endpoint was lower in one of the treatment arms, it was always the arm with the lower achieved blood pressure that had the better clinical outcome.9-11,15,17
Marya Ostrowski, JFP Editor
With only 50% of patients typically taking their medications as prescribed and the cost of poor adherence reaching an estimated $177 billion annually in direct and indirect health care costs, one medication safety group is saying enough is enough.
The National Council on Patient Information and Education (NCPIE), a nonprofit coalition that includes health professional associations, government agencies, and pharmaceutical companies, issued a report this summer detailing a 10-step action plan for reducing the adverse health and economic consequences of poor medication adherence.
The plan, developed by a panel of experts that NCPIE convened, calls on the government and health care community to, among other things:
- address the barriers to patient adherence for patients with low health literacy.
- develop a curriculum on medication adherence for use in medical schools.
- mount a unified national education campaign to make patient adherence a national health priority.
“Medication adherence is America’s new drug problem,” said Carolyn M. Clancy, MD, director of the Agency for Healthcare Research and Quality. AHRQ has been working with NCPIE, the FDA, and the National Consumers League to develop a public education campaign on medication adherence, according to Clancy. The NCPIE report helps to bolster those ongoing efforts, she said.
On the heels of the report, NCPIE is planning on releasing videos that will teach seniors about properly taking their medications, according to Ray Bullman, NCPIE’s executive vice president.
To learn more about NCPIE’s initiatives, or for a copy of the report, Enhancing Prescription Medicine Adherence: A National Action Plan, point your browser to: www.talkaboutrx.org.
These achieved blood pressure differences although small, were significant. Small overall mean blood pressure differences could mask much larger blood pressure differences in the individual patient. Consider, for instance, the HOPE (Heart Outcomes Prevention Evaluation) trial, where a reported overall blood pressure difference of only 3/1 mm Hg between the 2 treatment arms masked a difference of 10/4 mm Hg in 24-hour ambulatory blood pressure and a difference of 17/8 mm Hg in night-time blood pressure.39,40
Thus, instead of trying to work out why antihypertensive drugs could exert apparently different cardiovascular protective efficacy in different trials, the simple and consistent message is that the lower the achieved blood pressure, the lower the adverse clinical cardiovascular outcome.
What makes sense for your patient?
In selecting antihypertensive drugs, physicians should be guided by data supporting a particular drug in coexisting clinical conditions. (See “Where to begin when there are coexisting conditions,”.) In the hypertensive patient who is free of clinical disease, a case can be made for a diuretic as the first-line drug, although calcium channel blockers, ARBs, and ACE inhibitors can also claim evidence to support their use. In the older patient, beta-blockers—especially atenolol—should not be the drug of first choice.35,36,41
As this review of comparative hypertension drug trials shows, multiple drugs are required for adequate blood pressure control in most patients. Thus, physicians should not be too preoccupied about how to initiate treatment, but remember to add drugs until adequate control is achieved.
Correspondence
H T Ong, FRCP, FACC, FESC, H T Ong Heart Clinic, 251C Burma Road, Penang 10350, Malaysia; [email protected]
- In your efforts to reduce cardiovascular events in hypertensive patients, concentrate on getting patients to goal, rather than on which drugs to use to get them there (A).
- Beta-blockers—especially atenolol—should not be the drug of first choice when treating older patients with hypertension (A).
- Multiple drugs are required for adequate blood pressure control in most patients (A).
Strength of recommendation (SOR)
- Good quality patient-oriented evidence
- Inconsistent or limited-quality patient-oriented evidence
- Consensus, usual practice, opinion, disease-oriented evidence, case series
Forget about a silver bullet.
Researchers have conducted numerous trials over the last decade to find an antihypertensive drug that best reduces cardiovascular events while reducing blood pressure. However, this objective review of 13 comparative antihypertensive drug trials over the past decade involving more than 168,000 patients reveals no great differences in the cardiovascular protective effects of diuretics, beta-blockers, calcium channel blockers, angiotensin receptor blockers (ARBs), and angiotensin-converting enzyme (ACE) inhibitors.
In fact, this review indicates that there were no significant differences in the primary cardiovascular endpoints in more than 90% of the patients studied. Where a difference in secondary clinical outcome was demonstrated, fewer events consistently occurred in the regimen that reached the lower blood pressure level.
This assessment will likely fly in the face of the way that many would view this body of research. That’s understandable. At first glance, it would appear that these 13 trials, with different methodology and endpoints, have produced conflicting conclusions with the confusion worsened by pharmaceutical companies seeking to interpret the results to best suit their marketing needs.1-3
It is not the quality of the data, however, that is in question; the controversy lies in the interpretation. Subjecting the studies to further statistical analysis would simply obscure the information.
By reviewing the data impartially and objectively as a whole, though, and interpreting individual studies in light of similar studies, it becomes evident that there is more consensus than conflict. The studies support the notion that we should concentrate on getting patients to goal, rather than focusing on which drugs we’ll use to get them there.
Methods
I performed a PubMed search of the last 10 years using the keywords hypertension, comparative, drug trials. I supplemented my search with references from the JNC 7, WHO, BHS/NICE, and European hypertension guidelines. For this review, I included only randomized controlled trials with clinical cardiovascular primary endpoints. The studies had to have enrolled at least 500 patients and followed them for at least 3 years. Thirteen trials satisfied these criteria.4-17 All 13 are summarized in the TABLE, but I will review 5 of the more recent trials here. They are:
- ASCOT-BPLA—Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm
- ALLHAT—Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial
- ANBP2—Second Australian National Blood Pressure Study
- LIFE—Losartan Intervention For Endpoint reduction
- VALUE—Valsartan Antihypertensive Long-term Use Evaluation.
Calcium channel blockers vs beta-blockers
ASCOT-BPLA studied 19,257 high-risk hypertensive patients on amlodipine (Norvasc), adding perindopril, or atenolol (Tenormin), adding bendroflumethiazide.17 After 5.5 years, the primary end-point of nonfatal myocardial infarction (MI) and cardiovascular death was similar (relative risk [RR]=0.90; 95% confidence interval [CI], 0.79–1.02; P=.1052).
Total coronary endpoint, stroke, and mortality were all lower on amlodipine. Blood pressure was significantly lower on amlodipine compared with atenolol, with an average difference of 2.7/1.9 mm Hg over the trial duration.18
At the end of the trial, patients on amlodipine also had a significantly higher HDL cholesterol, and lower body mass index, triglyceride, creatinine, and glucose levels. However, when researchers made a multivariate adjustment for all of these risk factors, cardiovascular event rate differences between the 2 groups disappeared, underscoring the importance of controlling for all risk factors in reducing clinical cardiovascular events.18,19
A careful reading of ASCOT-BPLA, then, makes it clear that this study does not support the notion that newer antihypertensives (calcium channel blockers and ACE inhibitors) are superior to older ones (beta-blockers and diuretics).20,21 This study actually demonstrates that while blood pressure reduction is vital, the differences between regimens are less important.
TABLE
More consensus than conflict among 13 comparative antihypertensive drug trials with cardiovascular primary endpoints
| YEAR | TRIAL | N | DRUGS COMPARED | PRIMARY ENDPOINT | RELATIVE RISK (95% CI) | P VALUE |
|---|---|---|---|---|---|---|
| 1998 | UKPDS4 | 758 | Captopril vs atenolol | Clinical diabetic event | 1.1 (0.86–1.41) | .43 |
| Diabetic death | 1.27 (0.82–1.97) | .28 | ||||
| Total mortality | 1.14 (0.81–1.61) | .44 | ||||
| 1999 | CAPPP5 | 10,985 | Captopril vs diuretic/beta-blocker | MI+stroke+CV death | 1.05 (0.90–1.22) | .52 |
| 1999 | STOP 26 | 6614 | New vs conventional drugs | CV death | 0.99 (0.84–1.16) | .89 |
| 4418 | ACE I vs conventional drugs | CV death | 1.01 (0.84–1.22) | .89 | ||
| 4409 | CCB vs conventional drugs | CV death | 0.97 (0.80–1.17) | .72 | ||
| 2000 | INSIGHT7 | 6321 | Nifedipine LA vs diuretic | CV death, MI, HF, stroke | 1.1 (0.91–1.34) | .35 |
| 2000 | NORDIL8 | 10,881 | Diltiazem vs beta-blocker/diuretic | Stroke, MI, CV death | 1.00 (0.87–1.15) | .97 |
| 2002 | LIFE9 | 9193 | Losartan vs atenolol | CV death, stroke, MI | 0.87 (0.77–0.98) | .021 |
| 2002–3 | ALLHAT10,11 | 24,303 | Amlodipine vs chlorthalidone | Fatal CHD, nonfatal MI | 0.98 (0.90–1.07) | .65 |
| 24,309 | Lisinopril vs chlorthalidone | Fatal CHD, nonfatal MI | 0.99 (0.91–1.08) | .81 | ||
| 24,314 | Doxazosin vs chlorthalidone | Fatal CHD, nonfatal MI | 1.03 (0.93–1.15) | .62 | ||
| 2003 | ANBP212 | 6083 | ACE I vs diuretic | CV event,* death | 0.89 (0.79–1.00) | .05 |
| 2003 | CONVINCE13 | 16,602 | Verapamil vs atenolol/thiazide | Stroke, MI, CV death | 1.02 (0.88–1.18) | .77 |
| 2003 | INVEST14 | 22,576 | Verapamil vs atenolol | Death, nonfatal MI, nonfatal stroke | 0.98 (0.90–1.06) | .57 |
| 2004 | VALUE15 | 15,245 | Valsartan vs amlodipine | CV event† | 1.04 (0.94–1.15) | .49 |
| 2004 | JMIC-B16 | 1650 | Nifedipine retard vs ACE I | Cardiac events‡ | 1.05 (0.81–1.37) | .86 |
| 2005 | ASCOT17 | 19,257 | Amlodipine (+ perindopril) vs atenolol (+ thiazide) | Nonfatal MI, fatal CHD | 0.90 (0.79–1.02) | .1052 |
| ACE I, angiotensin-converting enzyme inhibitor; CCB, calcium channel blocker; CHD, coronary heart disease; CI, confidence interval; CV, cardiovascular; HF, heart failure; MI, myocardial infarction. | ||||||
| *Defined as coronary events including MI, heart failure, acute occlusion of artery, dissecting or ruptured aortic aneurysm, and cerebrovascular events including stroke and transient ischemic attacks. | ||||||
| † Defined as cardiac death, hospitalized heart failure, nonfatal MI, and emergency procedures to prevent MI. | ||||||
| ‡ Defined as cardiac death or sudden death, MI, angina pectoris requiring hospitalization, heart failure requiring hospitalization, serious arrhythmia, and coronary interventions. | ||||||
Largest hypertensive trial ever studied 4 drugs
ALLHAT, the largest hypertensive trial ever conducted, randomized 15,255 patients to chlorthalidone, 9061 to doxazosin (Cardura), 9048 to amlodipine, and 9054 to lisinopril (Prinivil/Zestril).10,11 (The arm involving doxazosin was terminated after 3.2 years.11,22)
Compared with the beta-blocker, more patients achieved target blood pressure control on chlorthalidone (63% vs 58%), and systolic blood pressure was about 2 mm Hg lower. Although the primary outcome of fatal coronary heart disease and nonfatal MI was equal in both groups (doxazosin=7.91%; chlorthalidone=7.76%; RR=1.03 [95% CI, 0.93–1.15]; P=.62), the doxazosin arm had more stroke, heart failure, and combined cardiovascular events.
Patients on amlodipine and lisinopril had a longer follow-up of 4.9 years. Systolic blood pressure was higher on amlodipine (0.8 mm Hg, P=.03) and lisinopril (2 mm Hg, P<.001) than on chlorthalidone. The primary endpoint (fatal coronary heart disease and nonfatal MI) was similar on the diuretic (11.5%), calcium channel blocker (11.3%; RR=0.98 [95% CI, 0.90–1.07]; P=.65), and ACE inhibitor (11.4%; RR=0.99 [95% CI, 0.91–1.08]; P=.81).
Compared with the diuretic arm, the calcium channel blocker arm had a higher incidence of heart failure, while the ACE inhibitor arm had a higher incidence of heart failure, stroke, and combined cardiovascular disease. The results were similar whatever the initial glycemic state, renal function status, and racial makeup of the patients studied.23-26 More than 60% of patients in ALLHAT required 2 or more drugs for good blood pressure control.27
“Diuretics first” for patients with or without diabetes?
In ALLHAT, although diabetes occurred more frequently and fasting glucose rose in patients on diuretics, these metabolic abnormalities did not result in more cardiovascular events. Even among patients with diabetes, heart failure was more common on doxazosin, amlodipine, and lisinopril compared with those on chlorthalidone.23,24
Given that the ultimate aim of hypertensive therapy is to reduce clinical disease—not just to improve laboratory profiles—ALLHAT should put to rest any apprehension physicians have about diuretic use. These findings have even led to suggestions that diuretics be the first line antihypertensive agent, in both diabetic and nondiabetic patients.28-30
ACE inhibitor vs diuretic
ANBP2 randomized hypertensive patients to initial treatment with an ACE inhibitor (n=3044) or a diuretic (n=3039).12 With similar blood pressure reduction in both arms (26/12 mm Hg), treatment with the ACE inhibitor resulted in a lower incidence of the composite primary end-point of cardiovascular events or total death that was of borderline significance (ACE inhibitor=22.8%; diuretic=24.2%; RR=0.89 [95% CI, 0.79–1.00]; P=.05).
Among women, there was no difference between the ACE inhibitor and diuretic groups. In the overall population, there was also no difference individually of total mortality or incidence of first cardiovascular event or death.
Thus ANBP2 actually confirms the results from ALLHAT by showing that ACE inhibitors and diuretics are equivalent in reducing cardiovascular events in hypertension.31
Losartan vs atenolol
In the LIFE study, 9193 hypertensive patients with left ventricular hypertrophy were randomized to either losartan (Cozaar) or atenolol.9 Losartan treatment resulted in a marked reduction in stroke incidence, which produced a significant reduction in the composite primary end-point of death, MI, or stroke (11% vs 13%; RR=0.87 [95% CI, 0.77–0.98]; P=.021).
When only the 1195 patients with diabetes were assessed, there was a significant reduction not only in the primary endpoint but also in cardiovascular and total mortality.32 Surprisingly, the reduction of stroke incidence did not reach statistical significance in this diabetic population (RR=0.79 [95% CI, 0.55–1.14]; P=.204).
A word of caution, though: The results of LIFE should be taken together with data from other trials. No other study has demonstrated a special benefit from the renin-angiotensin antagonists in preventing stroke. In fact, ACE inhibitors were weaker than the comparator drugs in preventing stroke in both CAPPP (TABLE) and ALLHAT.5,10 Various reviews have suggested that among antihypertensive drugs, it is the diuretics and calcium channel blockers that may be more useful in stroke reduction.33,34
Chalk the benefit up to the drop in blood pressure
In the LIFE study, the treated mean systolic blood pressure was lower with losartan in the overall (1.1 mm Hg; P=.017) and diabetic (2 mm Hg; P value not stated) populations, and thus the clinical benefit could possibly have been from the better blood pressure reduction on losartan. Furthermore, there is evidence that beta-blockers are less useful in the older hypertensive patient, and are especially weak in preventing stroke incidence.35,36
Rather than showing the superiority of the ARB, it is fair to say that LIFE actually confirms the importance of blood pressure reduction, and reveals the weaker cardiovascular protective effect of atenolol in older hypertensive patients.
Valsartan, amlodipine in high-risk patients
VALUE randomized 15,245 high-risk hypertensive patients to valsartan (Diovan) and amlodipine.15,37 Trial researchers sought to study the difference—for the same level of blood pressure reduction—between the 2 regimens in the incidence of cardiac events defined as sudden cardiac death, hospitalized heart failure, nonfatal MI, and emergency procedures to prevent MI. That said, the attained blood pressure was lower on the calcium channel blocker: 4.0/2.1 mm Hg at 1 month and 2.1/1.7 mm Hg at the end of study.
After 4.2 years, there was no significant difference in the primary endpoint of first cardiac event (10.6% valsartan/10.4% amlodipine; RR=1.04 [95% CI, 0.94–1.15]; P=.49). Diabetes was lower, but the rate of MI was higher on valsartan. After correction for the blood pressure difference, the composite of cardiac events, stroke, death, or MI was similar in the 2 groups.38
VALUE patients reaching adequate blood pressure control by 6 months fared better, regardless of drug type used. Thus demonstrating that the benefit from good blood pressure control was more important than the subtle differences between antihypertensive drugs. The better metabolic profile in the angiotensin receptor blocker arm did not translate into a reduction in adverse clinical disease.
The VALUE trial suggests (as did ALLHAT) that drugs targeting the reninangiotensin system do not provide special cardiovascular protection.10,15
Choosing an antihypertensive drug according to the clinical disease and target organ most at risk of damage is logical and in keeping with numerous guidelines.42-45 Thus, you’ll want to treat hypertensive patients with these conditions as follows:
- Angina pectoris. Therapy should include a beta-blocker or calcium channel blocker, given their definite antianginal and possible anti-atherosclerotic effects.16,46,47
- Prior MI. Start the patient on a beta-blocker.47
- Poor left ventricular function. Start the patient on a diuretic, and then add an ACE inhibitor and beta-blocker, as needed.10,49,50
- Prior stroke (or a patient at special risk of stroke). Begin therapy with a calcium channel blocker or a diuretic.33,34
- Diabetic proteinuria. An ARB or an ACE inhibitor is best suited to prevent and delay nephropathy.51-54
Consensus emerges from studies spanning 10 years
This objective review of the comparative hypertension drug trials shows that there are no great differences in the cardiovascular protective efficacy of the diuretics, beta-blockers, calcium channel blockers, ARBs, and ACE inhibitors.
There was no significant difference in the cardiovascular primary endpoint in 11 of the 13 trials reviewed, involving 91% of the randomized 168,593 patients (TABLE).4-8,10,11,13-17 Of the remaining 2 trials, the difference in ANBP2 just reached a P value of .05, while the result in LIFE was driven by a lower stroke incidence on ARB treatment that is not noted in any of the other studies involving an ARB or ACE inhibitor.4-6,10,12-15
Focus on controlling blood pressure with combination of drugs
Given the very large number of patients studied in these well-conducted trials, if there were any especially useful, or detrimental, cardiovascular effect of a particular class of antihypertensive drug, it would have been obvious by now. Since most patients will require multiple drugs, the equivalent protective efficacy of different antihypertensive drugs is reassuring and suggests that physicians should not worry too much about which drug to start the patient on.28 Rather, the emphasis should be on how best to reach adequate blood pressure control by combining several antihypertensive drugs.
Small blood pressure differences, big impact
In LIFE (losartan vs atenolol), ALLHAT (doxazosin, amlodipine, lisinopril vs chlorthalidone), VALUE (amlodipine vs valsartan), and ASCOT (amlodipine vs atenolol), where a secondary cardiovascular endpoint was lower in one of the treatment arms, it was always the arm with the lower achieved blood pressure that had the better clinical outcome.9-11,15,17
Marya Ostrowski, JFP Editor
With only 50% of patients typically taking their medications as prescribed and the cost of poor adherence reaching an estimated $177 billion annually in direct and indirect health care costs, one medication safety group is saying enough is enough.
The National Council on Patient Information and Education (NCPIE), a nonprofit coalition that includes health professional associations, government agencies, and pharmaceutical companies, issued a report this summer detailing a 10-step action plan for reducing the adverse health and economic consequences of poor medication adherence.
The plan, developed by a panel of experts that NCPIE convened, calls on the government and health care community to, among other things:
- address the barriers to patient adherence for patients with low health literacy.
- develop a curriculum on medication adherence for use in medical schools.
- mount a unified national education campaign to make patient adherence a national health priority.
“Medication adherence is America’s new drug problem,” said Carolyn M. Clancy, MD, director of the Agency for Healthcare Research and Quality. AHRQ has been working with NCPIE, the FDA, and the National Consumers League to develop a public education campaign on medication adherence, according to Clancy. The NCPIE report helps to bolster those ongoing efforts, she said.
On the heels of the report, NCPIE is planning on releasing videos that will teach seniors about properly taking their medications, according to Ray Bullman, NCPIE’s executive vice president.
To learn more about NCPIE’s initiatives, or for a copy of the report, Enhancing Prescription Medicine Adherence: A National Action Plan, point your browser to: www.talkaboutrx.org.
These achieved blood pressure differences although small, were significant. Small overall mean blood pressure differences could mask much larger blood pressure differences in the individual patient. Consider, for instance, the HOPE (Heart Outcomes Prevention Evaluation) trial, where a reported overall blood pressure difference of only 3/1 mm Hg between the 2 treatment arms masked a difference of 10/4 mm Hg in 24-hour ambulatory blood pressure and a difference of 17/8 mm Hg in night-time blood pressure.39,40
Thus, instead of trying to work out why antihypertensive drugs could exert apparently different cardiovascular protective efficacy in different trials, the simple and consistent message is that the lower the achieved blood pressure, the lower the adverse clinical cardiovascular outcome.
What makes sense for your patient?
In selecting antihypertensive drugs, physicians should be guided by data supporting a particular drug in coexisting clinical conditions. (See “Where to begin when there are coexisting conditions,”.) In the hypertensive patient who is free of clinical disease, a case can be made for a diuretic as the first-line drug, although calcium channel blockers, ARBs, and ACE inhibitors can also claim evidence to support their use. In the older patient, beta-blockers—especially atenolol—should not be the drug of first choice.35,36,41
As this review of comparative hypertension drug trials shows, multiple drugs are required for adequate blood pressure control in most patients. Thus, physicians should not be too preoccupied about how to initiate treatment, but remember to add drugs until adequate control is achieved.
Correspondence
H T Ong, FRCP, FACC, FESC, H T Ong Heart Clinic, 251C Burma Road, Penang 10350, Malaysia; [email protected]
1. Psaty BM, Weiss NS, Furberg CD. Recent trials in hypertension. Compelling science or commercial speech? JAMA 2006;295:1704-1706.
2. Abramson J, Starfield B. The effect of conflict of interest on biomedical research and clinical practice guidelines: Can we trust the evidence in evidence-based medicine? J Am Board Fam Pract 2005;18:414-418.
3. Lexchin J, Bero LA, Djulbegovic B, Clark O. Pharmaceutical industry sponsorship and research outcome and quality: systematic review. BMJ 2003;326:1167-1170.
4. UK Prospective Diabetes Study Group. Efficacy of Atenolol and Captopril in Reducing Risk of Macrovascular and Microvascular Complications in Type 2 Diabetes: UKPDS 39. BMJ 1998;317:713-720.
5. Hansson L, Lindholm LH, Niskanen L, et al. Effect of ACE inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: The Captopril Prevention Project (CAPPP). Lancet 1999;353:611-616.
6. Hansson L, Lindholm LH, Ekbom T, et al. Randomized trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity the Swedish Trial in Old Patients with Hypertension 2 (STOP-Hypertension 2) study. Lancet 1999;354:1751-1756.
7. Brown MJ, Palmer CR, Castaigne A, et al. Morbidity and mortality in patients randomized to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT). Lancet 2000;356:366-372.
8. Hansson L, Hedner T, Lund-Johansen P, et al. For the NORDIL Study Group. Randomised trial of effects of calcium antagonists compared with diuretics and beta-blockers on cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazem (NORDIL) Study. Lancet 2000;356:359-365.
9. Dahlof B, Devereux RB, Kjeldsen SE, et al. For the LIFE study group. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomized trial against atenolol. Lancet 2002;359:995-1003.
10. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to prevent Heart Attack trial (ALLHAT). JAMA 2002;288:2981-2997.
11. ALLHAT officers and Coordinators for the ALLHAT Collaborative research Group. Diuretic versus alpha-blocker as first-step antihypertensive therapy: final results from the Antihypertensive and lipidlowering treatment to prevent Heart Attack trial (ALLHAT). Hypertension 2003;42:239-246.
12. Wing LMH, Reid CM, Ryan P, et al. For the Second Australian National blood pressure Study Group. A comparison of outcomes with angiotensin converting enzyme inhibitors and diuretics for hypertension in the elderly. N Engl J Med 2003;348:583-592.
13. Black HR, Elliott WJ, Grandits G, et al. For the CONVINCE research Group. Principal results of the Controlled ONset Verapamil INvestigation of Cardiovascular End points (CONVINCE) trial. JAMA 2003;289:2073-2082.
14. Pepine CJ, Handberg EM, Cooper-DeHoff RM, et al. For the INVEST Investigators. A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil-Trandolapril Study (INVEST): A randomized controlled trial. JAMA 2003;290:2805-2816.
15. Julius S, Kjeldsen SE, Weber M. for the VALUE trial group. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomized trial. Lancet 2004;363:2022-2031.
16. Yui Y, Sumiyoshi T, Kodama K, et al. Comparison of nifedipine retard with angiotensin-converting enzyme inhibitors in Japanese hypertensive patients with coronary artery disease: the Japan multicenter Investigation for Cardiovascular Diseases-B (JMIC-B) randomized trial. Hypertens Res 2004;27:181-191.
17. Dahlof B, Sever PS, poulter NR. for the ASCOT investigators. prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac outcomes trial-blood pressure lowering Arm (ASCOT-BPLA): a multicentre randomized controlled trial. Lancet 2005;366:895-906.
18. Poulter NR, Wedel H, Dahlof B. For the ASCOT investigators. Role of blood pressure and other variables in the differential cardiovascular event rates noted in the Anglo-Scandinavian Cardiac outcomes trial-blood pressure lowering Arm (ASCOT-BPLA). Lancet 2005;366:907-913.
19. Daviglus ML, Liu K. today’s Agenda. We must focus on achieving favorable levels of all risk factors simultaneously. Arch Intern Med 2004;164:2086-2087.
20. Duerden M. ASCOT-BPLA. Lancet 2006;367:206.-
21. Cave JA. ASCOT: A tale of two treatment regimes. Is ASCOT all it’s cracked up to be? BMJ 2005;331:1023.-
22. The ALLHAT officers and Coordinators for the AllHAt Collaborative research Group. Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2000;283:1967-1975.
23. Barzilay JI, Davis BR, Bettencourt J, et al. For the ALLHAT Collaborative research Group. Cardiovascular outcomes using doxazosin vs chlorthalidone for the treatment of hypertension in older adults with and without glucose disorders: a report from the ALLHAT Study. J Clin Hypertens 2004;6:116-125.
24. Whelton PK, Barzilay J, Cushman WC, et al. For the ALLHAT Collaborative research group. Clinical outcomes in antihypertensive treatment of type 2 diabetes, impaired fasting glucose concentration, and normoglycemia. Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Arch Intern Med. 2005;165:1401-1409.
25. Rahman M, Pressel S, Davis BR, et al. For the ALLHAT Collaborative research Group. Renal outcomes in high-risk hypertensive patients treated with an angiotensin-converting enzyme inhibitor or a calcium channel blocker vs a diuretic: a report from the ALLHAT Study. Arch Inten Med 2005;165:936-946.
26. Wright JT, Dunn JK, Cutler JA, et al. for the ALLHAT Collaborative research Group. outcomes in hyper-tensive black and nonblack patients treated with chlorthalidone, amlodipine, and lisinopril. JAMA 2005;293:1595-1607.
27. Cushman WC, Ford CE, Cutler JA, et al. Success and predictors of blood pressure control in diverse North American settings: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). J Clin Hypertens 2002;4:393-504.
28. Williams B. Drug treatment for hypertension: most patients will need a treatment cocktail –including a thiazide diuretic. BMJ 2003;326:61-62.
29. Appel LJ. the verdict from ALLHAT—thiazide diuretics are the preferred initial therapy for hypertension. JAMA 2002;288:3039-3042.
30. Salvetti A, Ghiadoni L. Guidelines for antihypertensive treatment: An update after the ALLHAT study. J Am Soc Nephrol 2004;15:S51-S54.
31. Frohlich ED. Treating hypertension-what are we to believe? N Engl J Med 2003;348:639-641.
32. Lindholm LH, Ibsen H, Dahlof B, et al. For the LIFE study group. Cardiovascular morbidity and mortality in patients with diabetes in the losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomized trial against atenolol. Lancet 2002;359:1004-1010.
33. Messerli FH, Grossman E, Lever AF. Do thiazide diuretics confer specific protection against strokes? Arch Intern Med 2003;163:2557-2560.
34. Opie LH, Schall R. Evidence-based evaluation of calcium channel blockers for hypertension. J Am Coll Cardiol 2002;39:315-322.
35. Carlberg B, Samuelsson O, Lindholm LH. Atenolol in hypertension: is it a wise choice? Lancet 2004;364:1684-1689.
36. Khan N, McAlister FA. Re-examining the efficacy of beta-blockers for the treatment of hypertension: a meta-analysis. CMAJ 2006;174:1737-1742.
37. Kjeldsen SE, Julius S, Brunner H, et al. for the VALUE Trial Group. Characteristics of 15314 hypertensive patients at high coronary risk. the VALUE trial. Blood Press 2001;10:83-91.
38. Weber MA, Julius S, Kjeldsen SE, et al. Blood pressure dependent and independent effects of antihypertensive treatment on clinical events in the VALUE trial. Lancet 2004;363:2049-2051.
39. The Heart outcomes prevention evaluation Study Investigators. Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000;342:145-153.
40. Svensson P, De Faire U, Sleight P, Yusuf S, Ostergren J. Comparative effects of ramipril on ambulatory and office blood pressures: a Hope substudy. Hypertension 2001;38:28-32.
41. Ong HT. Beta-blockers in hypertension and cardiovascular disease. BMJ 2007;334:946-949.
42. Chobanian AV, Bakris GL, Black HR, et al. The National High blood pressure education program Coordinating Committee.The Seventh report of the Joint National Committee on prevention, Detection, evaluation, and treatment of High blood pressure. the JNC 7 report. JAMA 2003;289:2560-2572.
43. Guidelines Committee. 2003 european Society of Hypertension-european Society of Cardiology guidelines for the management of arterial hypertension. J Hypertens 2003;21:1011-1053.
44. World Health Organization. International Society of Hypertension Writing Group. 2003 World Health Organisation (WHO)/International Society of Hypertension (ISH) statement on management of hypertension. J Hypertens 2003;21:1983-1992.
45. Williams B, Poulter NR, Brown MJ, et al. Guidelines for management of hypertension: report of the fourth working party of the british Hypertension Society, 2004—BHS IV. J Hum Hypertens 2004;18:139-185.
46. Nissen SE, Tuzcu EM, Libby P. for the CAMELOT investigators. effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure. the CAMELOT Study: a randomized controlled trial. JAMA 2004;292:2217-2226.
47. Hedblad B, Wikstrand J, Janzon L, Wedel H, Berglund G. Low dose Metoprolol CR/XL and Fluvastatin slow progression of carotid intima-media thickness: main results from the beta-blocker Cholesterol-lowering Asymptomatic plaque Study (BCAPS). Circulation 2001;103:1721-1726.
48. Freemantle N, Cleland J, Young P, Mason J, Harrison J. Beta-blockade after myocardial infarction: systematic review and meta regression analysis. BMJ 1999;318:1730-1737.
49. The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 1992;372:685-691.
50. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: metoprolol CR/XL randomised Intervention trial in Congestive Heart Failure (MERIT-HF). Lancet 1999;353:2001-2006.
51. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345:851-860.
52. Parving HH, Lehnert H, Mortensen JB, et al. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001;345:870-878.
53. Brenner BM, Cooper ME, Zeeuw D de, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345:861-869.
54. Wright JT, Bakris G, Greene T, et al. For the African American Study of Kidney Disease and Hypertension Study Group. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. JAMA 2002;288:2421-2431.
1. Psaty BM, Weiss NS, Furberg CD. Recent trials in hypertension. Compelling science or commercial speech? JAMA 2006;295:1704-1706.
2. Abramson J, Starfield B. The effect of conflict of interest on biomedical research and clinical practice guidelines: Can we trust the evidence in evidence-based medicine? J Am Board Fam Pract 2005;18:414-418.
3. Lexchin J, Bero LA, Djulbegovic B, Clark O. Pharmaceutical industry sponsorship and research outcome and quality: systematic review. BMJ 2003;326:1167-1170.
4. UK Prospective Diabetes Study Group. Efficacy of Atenolol and Captopril in Reducing Risk of Macrovascular and Microvascular Complications in Type 2 Diabetes: UKPDS 39. BMJ 1998;317:713-720.
5. Hansson L, Lindholm LH, Niskanen L, et al. Effect of ACE inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: The Captopril Prevention Project (CAPPP). Lancet 1999;353:611-616.
6. Hansson L, Lindholm LH, Ekbom T, et al. Randomized trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity the Swedish Trial in Old Patients with Hypertension 2 (STOP-Hypertension 2) study. Lancet 1999;354:1751-1756.
7. Brown MJ, Palmer CR, Castaigne A, et al. Morbidity and mortality in patients randomized to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT). Lancet 2000;356:366-372.
8. Hansson L, Hedner T, Lund-Johansen P, et al. For the NORDIL Study Group. Randomised trial of effects of calcium antagonists compared with diuretics and beta-blockers on cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazem (NORDIL) Study. Lancet 2000;356:359-365.
9. Dahlof B, Devereux RB, Kjeldsen SE, et al. For the LIFE study group. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomized trial against atenolol. Lancet 2002;359:995-1003.
10. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to prevent Heart Attack trial (ALLHAT). JAMA 2002;288:2981-2997.
11. ALLHAT officers and Coordinators for the ALLHAT Collaborative research Group. Diuretic versus alpha-blocker as first-step antihypertensive therapy: final results from the Antihypertensive and lipidlowering treatment to prevent Heart Attack trial (ALLHAT). Hypertension 2003;42:239-246.
12. Wing LMH, Reid CM, Ryan P, et al. For the Second Australian National blood pressure Study Group. A comparison of outcomes with angiotensin converting enzyme inhibitors and diuretics for hypertension in the elderly. N Engl J Med 2003;348:583-592.
13. Black HR, Elliott WJ, Grandits G, et al. For the CONVINCE research Group. Principal results of the Controlled ONset Verapamil INvestigation of Cardiovascular End points (CONVINCE) trial. JAMA 2003;289:2073-2082.
14. Pepine CJ, Handberg EM, Cooper-DeHoff RM, et al. For the INVEST Investigators. A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil-Trandolapril Study (INVEST): A randomized controlled trial. JAMA 2003;290:2805-2816.
15. Julius S, Kjeldsen SE, Weber M. for the VALUE trial group. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomized trial. Lancet 2004;363:2022-2031.
16. Yui Y, Sumiyoshi T, Kodama K, et al. Comparison of nifedipine retard with angiotensin-converting enzyme inhibitors in Japanese hypertensive patients with coronary artery disease: the Japan multicenter Investigation for Cardiovascular Diseases-B (JMIC-B) randomized trial. Hypertens Res 2004;27:181-191.
17. Dahlof B, Sever PS, poulter NR. for the ASCOT investigators. prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac outcomes trial-blood pressure lowering Arm (ASCOT-BPLA): a multicentre randomized controlled trial. Lancet 2005;366:895-906.
18. Poulter NR, Wedel H, Dahlof B. For the ASCOT investigators. Role of blood pressure and other variables in the differential cardiovascular event rates noted in the Anglo-Scandinavian Cardiac outcomes trial-blood pressure lowering Arm (ASCOT-BPLA). Lancet 2005;366:907-913.
19. Daviglus ML, Liu K. today’s Agenda. We must focus on achieving favorable levels of all risk factors simultaneously. Arch Intern Med 2004;164:2086-2087.
20. Duerden M. ASCOT-BPLA. Lancet 2006;367:206.-
21. Cave JA. ASCOT: A tale of two treatment regimes. Is ASCOT all it’s cracked up to be? BMJ 2005;331:1023.-
22. The ALLHAT officers and Coordinators for the AllHAt Collaborative research Group. Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2000;283:1967-1975.
23. Barzilay JI, Davis BR, Bettencourt J, et al. For the ALLHAT Collaborative research Group. Cardiovascular outcomes using doxazosin vs chlorthalidone for the treatment of hypertension in older adults with and without glucose disorders: a report from the ALLHAT Study. J Clin Hypertens 2004;6:116-125.
24. Whelton PK, Barzilay J, Cushman WC, et al. For the ALLHAT Collaborative research group. Clinical outcomes in antihypertensive treatment of type 2 diabetes, impaired fasting glucose concentration, and normoglycemia. Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Arch Intern Med. 2005;165:1401-1409.
25. Rahman M, Pressel S, Davis BR, et al. For the ALLHAT Collaborative research Group. Renal outcomes in high-risk hypertensive patients treated with an angiotensin-converting enzyme inhibitor or a calcium channel blocker vs a diuretic: a report from the ALLHAT Study. Arch Inten Med 2005;165:936-946.
26. Wright JT, Dunn JK, Cutler JA, et al. for the ALLHAT Collaborative research Group. outcomes in hyper-tensive black and nonblack patients treated with chlorthalidone, amlodipine, and lisinopril. JAMA 2005;293:1595-1607.
27. Cushman WC, Ford CE, Cutler JA, et al. Success and predictors of blood pressure control in diverse North American settings: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). J Clin Hypertens 2002;4:393-504.
28. Williams B. Drug treatment for hypertension: most patients will need a treatment cocktail –including a thiazide diuretic. BMJ 2003;326:61-62.
29. Appel LJ. the verdict from ALLHAT—thiazide diuretics are the preferred initial therapy for hypertension. JAMA 2002;288:3039-3042.
30. Salvetti A, Ghiadoni L. Guidelines for antihypertensive treatment: An update after the ALLHAT study. J Am Soc Nephrol 2004;15:S51-S54.
31. Frohlich ED. Treating hypertension-what are we to believe? N Engl J Med 2003;348:639-641.
32. Lindholm LH, Ibsen H, Dahlof B, et al. For the LIFE study group. Cardiovascular morbidity and mortality in patients with diabetes in the losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomized trial against atenolol. Lancet 2002;359:1004-1010.
33. Messerli FH, Grossman E, Lever AF. Do thiazide diuretics confer specific protection against strokes? Arch Intern Med 2003;163:2557-2560.
34. Opie LH, Schall R. Evidence-based evaluation of calcium channel blockers for hypertension. J Am Coll Cardiol 2002;39:315-322.
35. Carlberg B, Samuelsson O, Lindholm LH. Atenolol in hypertension: is it a wise choice? Lancet 2004;364:1684-1689.
36. Khan N, McAlister FA. Re-examining the efficacy of beta-blockers for the treatment of hypertension: a meta-analysis. CMAJ 2006;174:1737-1742.
37. Kjeldsen SE, Julius S, Brunner H, et al. for the VALUE Trial Group. Characteristics of 15314 hypertensive patients at high coronary risk. the VALUE trial. Blood Press 2001;10:83-91.
38. Weber MA, Julius S, Kjeldsen SE, et al. Blood pressure dependent and independent effects of antihypertensive treatment on clinical events in the VALUE trial. Lancet 2004;363:2049-2051.
39. The Heart outcomes prevention evaluation Study Investigators. Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000;342:145-153.
40. Svensson P, De Faire U, Sleight P, Yusuf S, Ostergren J. Comparative effects of ramipril on ambulatory and office blood pressures: a Hope substudy. Hypertension 2001;38:28-32.
41. Ong HT. Beta-blockers in hypertension and cardiovascular disease. BMJ 2007;334:946-949.
42. Chobanian AV, Bakris GL, Black HR, et al. The National High blood pressure education program Coordinating Committee.The Seventh report of the Joint National Committee on prevention, Detection, evaluation, and treatment of High blood pressure. the JNC 7 report. JAMA 2003;289:2560-2572.
43. Guidelines Committee. 2003 european Society of Hypertension-european Society of Cardiology guidelines for the management of arterial hypertension. J Hypertens 2003;21:1011-1053.
44. World Health Organization. International Society of Hypertension Writing Group. 2003 World Health Organisation (WHO)/International Society of Hypertension (ISH) statement on management of hypertension. J Hypertens 2003;21:1983-1992.
45. Williams B, Poulter NR, Brown MJ, et al. Guidelines for management of hypertension: report of the fourth working party of the british Hypertension Society, 2004—BHS IV. J Hum Hypertens 2004;18:139-185.
46. Nissen SE, Tuzcu EM, Libby P. for the CAMELOT investigators. effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure. the CAMELOT Study: a randomized controlled trial. JAMA 2004;292:2217-2226.
47. Hedblad B, Wikstrand J, Janzon L, Wedel H, Berglund G. Low dose Metoprolol CR/XL and Fluvastatin slow progression of carotid intima-media thickness: main results from the beta-blocker Cholesterol-lowering Asymptomatic plaque Study (BCAPS). Circulation 2001;103:1721-1726.
48. Freemantle N, Cleland J, Young P, Mason J, Harrison J. Beta-blockade after myocardial infarction: systematic review and meta regression analysis. BMJ 1999;318:1730-1737.
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