What we &lt;i&gt;really&lt;/i&gt; need to do to reduce cardiovascular events in hypertensive patients

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Applied Evidence

What we really need to do to reduce cardiovascular events in hypertensive patients

J Fam Pract. 2007 September;56(9):727-734

By

H T Ong, FRCP (Glas

Edin), FACC, FESC

Treatment to goal is key—not which antihypertensive you start with, according to this review.

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References

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Practice recommendations

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.

FAST TRACK

More than 60% of the patients in one trial required 2 or more drugs for good blood pressure control

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	ALLHAT^10,11	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.