Cardiovascular disease and cancer are 2 of the leading causes of death globally. Certain cardiovascular medications have been linked to an increased risk for cancer. Although individual reviews of specific classes of cardiovascular medications have been published previously, a more complete review of several classes has not been performed. The aim of this review is to evaluate the associations of various cardiovascular agents with the risk for developing cancer and provide guidance for clinicians. A comprehensive search of published research was conducted using MEDLINE from 1994 to 2011. Three trials demonstrated an increased risk for cancer using angiotensin II receptor blockers. Additionally, risk for cancer was shown in a number of trials that included the use of angiotensin II receptor blockers in combination with angiotensin-converting enzyme inhibitors. Five trials suggested that diuretics increased the risk for specific cancers, especially in women and those who had been using diuretics for >4 years. Statins and ezetimibe, in contrast, did not show this increased risk. Prasugrel was shown to be associated with an increased risk for cancer in 1 study. It appears that the use of certain cardiovascular medications is associated with an increased risk for cancer. In conclusion, clinicians need to balance the risks and benefits of the use of these agents and provide the appropriate therapy on an individual basis.
Because the association between cardiovascular medications and cancer is still unclear, our goal was to further examine their relation. Because of a lack of data on all cardiovascular medications, we focused on medications with an abundant amount of published studies, such as angiotensin II receptor blockers (ARBs), diuretics, ezetimibe, statins, and prasugrel. The purpose of this review is to evaluate the effects of cardiovascular agents on cancer risk and to provide practical suggestions for clinicians in the medication management of patients with cardiovascular disease (CVD), while awaiting further studies.
Methods
A comprehensive search for publications on cardiovascular agents and cancer from 1994 to 2011 was conducted using MEDLINE. Randomized controlled trials, population-case studies, cohort studies, and meta-analyses were analyzed for this review. Meta-analyses and systematic reviews were used to obtain other randomized control trials, cohort studies, population-case studies, and meta-analyses.
Search terms were “antihypertensives,” “ARB,” “beta-adrenergic blockers,” “calcium channel blockers,” “diuretics,” “thiazide diuretics,” “statins,” “ezetimibe,” “prasugrel,” “clopidogrel,” “thienopyridines,” “cancer,” “neoplasm,” and “malignancy.” Additional studies were obtained from the reference lists of review articles and meta-analyses. Angiotensin-converting enzyme (ACE) inhibitors, β-adrenergic blockers, calcium channel blockers, and clopidogrel were excluded from this analysis because of the limited amount of studies examining the association of these agents with cancer risk.
Results
ARBs
ARBs work by blocking angiotensin II type 1 receptors. There are 8 ARBs on the market: azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, and valsartan. In a recent meta-analysis, Sipahi et al examined 93,515 subjects from 9 large randomized controlled trials and found that the use of ARBs was associated with an increased risk for new cancer and cancer deaths. Subjects who received ARBs, compared to those not on ARBs, had an increased risk for cancer (7.2% vs 6.0%). When the results were further divided to include only trials with cancer as a prespecified end point, the results demonstrated that there was an increased risk for cancer ( Table 1 ). Interestingly, there was a nonsignificant increase in the risk for death from cancer ( Table 1 ). Finally, after a review of the individual results, only the telmisartan plus ramipril arm of the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET) demonstrated a statistically significant increase in the risk for cancer ( Table 2 ).
| Variable | Risk Ratio (95% Confidence Interval) | p Value |
|---|---|---|
| Cancer occurrence in all trials | 1.08 (1.01–1.15) | 0.016 |
| Cancer as prespecified end point | 1.11 (1.04–1.18) | 0.001 |
| With background of ACE inhibitor treatment | 1.13 (1.03–1.24) | 0.011 |
| Without background of ACE inhibitor treatment | 1.08 (1.00–1.16) | 0.041 |
| Deaths from cancer | 1.07 (0.97–1.18) | 0.183 |
| Study | Year | n | Type of Study | Average Age (yrs) | Agent | Type of Cancer | Outcome | Increased Risk for Cancer |
|---|---|---|---|---|---|---|---|---|
| Kjeldsen et al (LIFE) | 2002 | 1,326 | RCT | 70 | Losartan | All | 9.8% vs 8.3% (p = 0.34) | No |
| Solomon et al (CHARM-Overall) | 2004 | 2,548 | RCT | — | ACE inhibitors and ARBs | All | HR 1.42, 95% CI 1.02–1.98 (p = 0.037) | Yes |
| Christian et al | 2008 | 1,051 | Cohort | 60–80 | ACE inhibitors and ARBs | Skin | BCC adjusted: IRR 0.61, 95% CI 0.5–0.76; SCC adjusted: IRR 0.67, 95% CI 0.52–0.87 | No |
| Yusuf et al (TRANSCEND) | 2008 | 5,926 | RCT | 67 | ARBs | All | HR 1.17, 95% CI 0.97–1.42 (p = 0.094) | No |
| Coleman et al | 2008 | 126,137 | Meta-analysis | — | ARBs | All | OR 1.12, 95% CI 0.87–1.47 | No |
| Solomon (ONTARGET) | 2008 | 25,620 | RCT | 66 | ACE inhibitors and ARBs | All | RR 1.14, 95% CI 1.03–1.26 | Yes |
| Assimes et al | 2008 | 11,697 | Case-control | — | ACE inhibitors and ARBs | All | OR 0.93, 95% CI 0.83–1.03 | No |
| Van der Knaap et al | 2008 | 7,983 | Cohort | ≥55 | ACE inhibitors and ARBs | All | HR 0.88, 95% CI 0.71–1.09 | No |
| Bangalore et al | 2010 | 324,168 | Meta-analysis | — | ARBs | All | OR 0.98, 95% CI 0.93–1.03 | No |
| Chin et al | 2011 | 3,288 | Cohort | 40 | ACE inhibitors and ARBS | All | ARB OR ⁎ 0.961, 95% CI 0.409–2.257; mortality: ARB OR: 0.124 (0.034–0.445) | No |
| Huang et al | 2011 | 109,002 | Cohort | 58 | ARBs | All | HR 0.5, 95% CI 0.46–0.53 (p <0.001) | No |
| Pasternak et al | 2011 | 425,285 | Cohort | ≥35 | ARBs | All | RR 0.99, 95% CI 0.95–1.03 | No |
| The ARB Trialists Collaboration | 2011 | 138,769 | Meta-analysis | — | ARBs | All | OR 1.00, 95% CI 0.95–1.04 (p = 0.886) | No |
In response to Sipahi et al’s findings, a meta-analysis was conducted examining 324,168 participants in 70 randomized controlled trials. This study further subdivided ARBs, investigating whether an ARB and ACE inhibitor combination had different cancer risk than ARB alone and whether telmisartan had a higher cancer risk compared to other ARBs. The study demonstrated that there was no increase in cancer risk for patients who were taking ARBs versus treatment control. However, similar to Sipahi et al’s meta-analysis there was an increased risk for cancer in patients who were taking ARBs in combination with ACE inhibitors, predominantly driven by the ONTARGET and Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity–Overall (CHARM-Overall) trials.
Two other studies, the Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (TRANSCEND) trial and the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study, showed nonsignificant increases in the risk for cancer in patients taking telmisartan (8.0%) compared to placebo (6.9%) and in patients taking losartan compared to atenolol (9.8% vs 8.3%, respectively).
Other studies have demonstrated that there is no increased risk for cancer in patients taking ARBs ( Table 2 ). In a recent Danish cohort study that included 425,285 subjects, ARBs were not associated with an increased risk for overall cancer. Other recent studies have suggested that ARBs reduce the risk for and mortality of cancer and that the reductions are related to the duration of use. Another recent review indicated that there is no additional risk for developing cancer using combination therapy with ARBs and ACE inhibitors.
Diuretics
Diuretics have been implicated in increasing the risk for cancers, especially in women. In earlier studies, involving case-control and cohort studies, diuretics were found to be associated with an increase in renal cell carcinomas. In 2 large studies that examined the risk for renal carcinomas from the use of diuretics, there was a 63% increase (statistically significant) ( Table 3 ) and 40% increase risk, which was not statistically significant ( Table 4 ), of renal carcinoma in women who were receiving diuretics. Data suggest that thiazide diuretics and high-ceiling diuretics are associated with increased risk for skin cell carcinomas. In a cohort study involving 40,656 subjects, there was an increased incidence of squamous cell carcinomas and malignant melanomas using hydrochlorothiazide, amiloride, or a combination of the 2. In another study with approximately 11,000 subjects, there was an increased risk for developing basal cell carcinoma using high-ceiling diuretics ( Table 3 ).
| Study | Year | n | Type of Study | Average Age (yrs) | Agent | Type of Cancer | Outcome | Comments |
|---|---|---|---|---|---|---|---|---|
| Tenenbaum et al | 2001 | 15,524 | ROS | 45–74 | Diuretics | All | HR 1.22, 95% CI 1.01–1.47; colon cancer: HR 1.96, 95% CI 1.21–3.17 | Yes |
| Largent et al | 2006 | 654 | Case-control | 50–75 | Diuretics | Breast | 185 (35.4%) vs 32 (24.4%) (p = 0.03) | Yes |
| Setiawan et al | 2007 | 215,000 | Cohort | 45–75 | Diuretics | Renal | Men: RR 1.06, 95% CI 0.74–1.52 ⁎ ; women: RR 1.63, 95% CI 1.04–2.57 ⁎ | Yes |
| Jensen et al | 2008 | 40,656 | Case-control | — | Diuretics | Skin (BCC, SCC, MM) | BCC: IRR 0.96, 95% CI 0.90–1.03; SCC: IRR 1.21, 95% CI 1.04–1.40; MM: IRR 1.19, 95% CI 1.01–1.41 | Yes |
| Ruiter et al | 2010 | 10,994 | Case-control | ≥55 | Diuretics | Skin (BCC) | HR 1.62, 95% CI 1.09–2.24 | Yes |
| Study | Year | n | Type of Study | Average Age | Agent | Type of Cancer | Outcome | Comments |
|---|---|---|---|---|---|---|---|---|
| ALLHAT | 2002 | 33,357 | RCT | ≥55 | ACE inhibitor vs diuretic, CCB vs diuretic | All | Lisinopril vs chlorthalidone: RR 1.02, 95% CI 0.93–1.12 (p = 0.67); amlodipine vs chlorthalidone: RR 1.01, 95% CI 0.92–1.11 (p = 0.77); cause of death: lisinopril vs chlorthalidone 297 (4%) vs 513 (4.3%) (p = 0.72); amlodipine vs chlorthalidone 280 (3.7%) vs 513 (4.3%) (p = 0.23) | No |
| Flaherty et al | 2005 | 167,144 | Cohort | 30–75 | Thiazide diuretics | Renal | Men: RR 0.8, 95% CI 0.5–1.5 ⁎ ; women: RR 1.4, 95% CI 0.9–2.3 ⁎ | No |
| Fryzek et al | 2006 | 19,284 | Cohort | 50–67 | Diuretics | Breast | RR 0.97, 95% CI 0.79–1.21 | No |
| Boudreau et al | 2008 | 1,330 | Case-control | 50–80 | Diuretics | Colorectal | OR 1.00, 95% CI 0.71–1.44 | No |
| Coleman et al | 2008 | 126,137 | Meta-analysis | — | Diuretics | All | OR 0.94, 95% CI 0.73–1.19 | No |
| Jiang et al | 2010 | 3,170 | Case-control | 25–64 | Diuretics | Bladder | OR 0.93, 95% CI 0.64–1.37 | No |
| Bangalore et al | 2010 | 324,168 | Meta-analysis | — | Diuretics | All | OR 0.98, 95% CI 0.84–1.13 | No |
Recent studies have suggested that diuretics are not associated with an increased overall risk for cancer ( Table 4 ). A meta-analysis by Coleman et al, which included 126,137 subjects, demonstrated that there was no increased risk for cancer with use of diuretics. This study was followed up by Bangalore et al’s meta-analysis, which also demonstrated that there was no increased risk for cancer associated with diuretic use.
Statins
Three-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, also known as statins, are the most commonly prescribed medications for the reduction of cholesterol in patients with dyslipidemia. There are 7 statins available on the market: lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin, rosuvastatin, and pitavastatin. There has been ongoing debate on whether or not statins affect the risk for developing cancer.
Early rodent studies have suggested that statins are oncogenic. In a case control study that assessed the risk for breast and prostate cancer in 2,141 patients, there was an increased risk for breast cancer in women who were using statins for >3 years, which showed statistical significance. An increase in prostate cancer risk was also seen in men but was not statistically significant. The Prospective Pravastatin Pooling (PPP) project found that statins may increase the incidence of breast cancer (0.2% in the pravastatin group vs 0.1% in the placebo group), which was statistically insignificant. Pravastatin was the most common statin linked to an increased risk for breast cancer. This may be due to pravastatin being more hydrophilic and more likely to induce mevalonate synthesis in tissues outside the liver, promoting the growth and proliferation of breast cancer cells.
Conversely, numerous recent studies have suggested that statins reduce cancer risks ( Table 5 ). The results of a cohort study demonstrated that there was no increased risk for cancer and concluded that the use of statins were found to have a statistically significant reduction in the overall risk for developing cancer. Another cohort study involving United States veterans also found a statistically significant decrease in the risk for cancer.
| Study | Year | n | Type of Study | Average Age (yrs) | Agent | Type of Cancer | Outcome | Comments |
|---|---|---|---|---|---|---|---|---|
| Coogan et al | 2002 | 4,859 | Case-control study | 50–79 | All statins | Breast and prostate | Breast cancer: OR 2.1, 95% CI 1.1–4.0; prostate cancer: OR 1, 95% CI 0.6–1.6 | Yes |
| Pfeffer et al | 2002 | 19,592 | Cohort | 59 | Pravastatin | Breast | Incidence 0.2% vs 0.1% (p = 0.08) | Yes |
| Friis et al | 2005 | 334,754 | Cohort | 30–80 | All statins | All | RR 0.86, 95% CI 0.78–0.95 | No ⁎ |
| Cauley et al | 2006 | 156,351 | Cohort | 50–79 | All statins | Breast | HR 0.91, 95% CI 0.8–1.05 (p = 0.2); using E + P: HR 0.93, 95% CI 0.74–1.18 | No ⁎ |
| Browning et al | 2006 | 103,573 | Meta-analysis | — | All statins | All | RR 0.95, 95% CI 0.87–1.03 (p = 0.14) | No ⁎ |
| Dale et al | 2006 | 86,936 | Meta-analysis | — | All statins | All | OR 1.02, 95% CI 0.97–1.07; deaths: OR 1.01, 95% CI 0.93–1.09 | Yes |
| Murtola et al | 2007 | 49,446 | Case-control | 20–96 | All statins | Prostate | OR 0.75, 95% CI 0.62–0.91 | No ⁎ |
| Farwell et al | 2008 | 62,842 | Cohort | 66 | All statins | All | 9.4% vs 13.2%; HR 3.8%, 95% CI 3.3% –4.3% (p <0.001); HR † 0.76, 95% CI 0.73–0.8 | No ⁎ |
| Chiu et al | 2010 | 2,332 | Case-control | ≥50 | All statins | Liver | OR 0.62, 95% CI 0.45–0.83 | No ⁎ |
| Bradley et al | 2010 | 9,095 | Case-control | ≥85 | All statins | Pancreas | OR 0.71, 95% CI 0.42–1.2 | No ⁎ |
| Samadder et al | 2010 | 3,842 | Case-control | ≥60 | Pravastatin and simvastatin | Colorectal | No IBD: OR 0.56, 95% CI 0.44–0.72; IBD: OR 0.10, 95% CI 0.01–1.31 | No ⁎ |
Ezetimibe
Ezetimibe blocks the absorption of cholesterol in the intestine through interactions with the Niemann-Pick C1-like 1 transporter. It is the only medication in its class and is approved for the treatment of primary hypercholesterolemia, familial hypercholesterolemia (homozygous), mixed hyperlipidemia, and homozygous familial sitosterolemia. Recent studies have suggested that the use of ezetimibe may be associated with an increased risk for cancer.
In the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial, which was a randomized controlled trial examining the effects of simvastatin plus ezetimibe on patients with asymptomatic aortic stenosis, ezetimibe was implicated to be associated with an increase in the incidence of cancer. The investigators found that 103 patients (11.1%) in the simvastatin-ezetimibe group compared to 65 (7.5%) patients in the placebo group had diagnoses of any cancer (p = 0.01), and 39 (4.1%) in the simvastatin-ezetimibe group compared to 23 (2.5%) in the placebo group had fatal cancers (hazard ratio 1.67, 95% confidence interval 1.00 to 2.79, p = 0.05). This finding led to a study that pooled the SEAS trial along with the Study of Heart and Renal Protection (SHARP) and the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) and demonstrated a nonsignificant increase in the risk for cancer in the ezetimibe group compared to control (relative risk 1.06, 95% confidence interval 0.92 to 1.22, p = 0.46).
Prasugrel
Prasugrel is the newest thienopyridine and is approved by the United States Food and Drug Administration for the reduction of thrombotic cardiovascular events in patients with acute coronary syndromes. Prasugrel has been shown to have greater platelet inhibition compared to clopidogrel and ticlopidine. However, prasugrel has been implicated in increasing the risk for cancer.
The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis In Myocardial Infarction 38 (TRITON–TIMI 38) was a randomized, double-blind, parallel-group, multinational clinical study that assessed the efficacy and safety of prasugrel compared to clopidogrel. Although the trial demonstrated that prasugrel had a lower rate of cardiovascular death, myocardial infarction, or stroke compared to clopidogrel, patients who were treated with prasugrel experienced a threefold higher rate of colonic neoplasm (13 vs 4 patients, p = 0.03). In an internal Food and Drug Administration document, 92 new solid cancers were found in the prasugrel group (1.4%) compared to 64 in the clopidogrel group (0.9%) (relative risk 1.44, p = 0.02). Further studies on the association of prasugrel with cancer risk are being conducted.
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